Substituted 6,7-dihydropyrazolo[1,5-a]pyrazines as negative allosteric modulators of mGluR2 receptors

ABSTRACT

The present invention relates to novel 6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one derivatives of Formula (I) 
                         
as negative allosteric modulators (NAMs) of the metabotropic glutamate receptor subtype 2 (“mGluR2”). The invention is also directed to pharmaceutical compositions comprising such compounds, to processes for preparing such compounds and compositions, and to the use of such compounds and compositions for the prevention or treatment of disorders in which the mGluR2 subtype of metabotropic receptors is involved.

This application is a continuation application of U.S. patentapplication Ser. No. 15/500,600 filed Jan. 31, 2017, which is a 371National Stage Application of PCT/EP2015/067530 with an internationalfiling date of Jul. 30, 2015, and claims the benefit of EP 14179598.9filed Aug. 1, 2014, the entire disclosures of each of which are herebyincorporated in their entirety.

FIELD OF THE INVENTION

The present invention relates to novel6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one derivatives as negativeallosteric modulators (NAMs) of the metabotropic glutamate receptorsubtype 2 (“mGluR2”). The invention is also directed to pharmaceuticalcompositions comprising such compounds, to processes for preparing suchcompounds and compositions, and to the use of such compounds andcompositions for the prevention or treatment of disorders in which themGluR2 subtype of metabotropic receptors is involved.

BACKGROUND OF THE INVENTION

The glutamatergic system in the CNS is one of the neurotransmittersystems that play a key role in several brain functions. Metabotropicglutamate receptors (mGluR) belong to the G-protein-coupled family, andeight different subtypes have been identified to date, which aredistributed to various brain regions (Ferraguti & Shigemoto, Cell &Tissue Research, 326:483-504, 2006). mGluRs participate in themodulation of synaptic transmission and neuronal excitability in the CNSby the binding of glutamate. This activates the receptor to engageintracellular signaling partners, leading to cellular events (Niswender& Conn, Annual Review of Pharmacology & Toxicology 50:295-322, 2010).

mGluRs are further divided into three subgroups based on theirpharmacological and structural properties: group-I (mGluR1 and mGluR5),group-II (mGluR2 and mGluR3) and group-III (mGluR4, mGluR6, mGluR7 andmGluR8). Group-II ligands, both orthosteric and allosteric modulating,are considered to be potentially useful in the treatment of variousneurological disorders, including psychosis, mood disorders, Alzheimerdisease and cognitive or memory deficiencies. This is consistent withtheir primary localisation in brain areas such as the cortex,hippocampus and the striatum (Ferraguti & Shigemoto, Cell & TissueResearch 326:483-504, 2006). Particularly antagonists and negativeallosteric modulators are reported to hold potential for the treatmentof mood disorders and cognitive or memory dysfunction. This is based onfindings with group-II receptor antagonists and negative allostericmodulators tested in laboratory animals subjected to a range ofexperimental conditions deemed relevant to these clinical syndromes(Goeldner et al, Neuropharmacology 64:337-346, 2013). Clinical trialsare, for example, underway with mGluR2/3 antagonist decoglurantRO4995819 (F. Hoffmann-La Roche Ltd.) in adjunctive therapy in patientswith Major Depressive Disorder having inadequate response to ongoingantidepressant treatment (ClinicalTrials.gov Identifier NCT01457677,retrieved 19 Feb. 2014). WO 2013066736 (Merck Sharp & Dohme Corp.)describes quinoline carboxamide and quinoline carbonitrile compounds asmGluR2 NAMs. WO2013174822 (Domain Therapeutics) describes4H-pyrazolo[1,5-a]quinazolin-5-ones and 4H-pyrrolo[1,2-a]quinazolin-5-ones and in vitro mGluR2 NAM activity thereof. WO2014064028 (F. Hoffman-La Roche AG) discloses a selection of mGlu2/3negative allosteric modulators and their potential use in the treatmentof Autistic Spectrum Disorders (ASD).

The group-II receptors are mainly located on presynaptic nerve terminalswhere they exert a negative feedback loop to the release of glutamateinto the synapse (Kelmendi et al, Primary Psychiatry 13:80-86, 2006).Functional inhibition of these receptors by antagonists or negativeallosteric modulators therefore lifts the brake on glutamate release,resulting in enhanced glutamatergic signaling. This effect is believedto underlie the antidepressant-like and procognitive effects observed inpreclinical species with inhibitors of the Group-II receptor. Inaddition, treatment of mice with group-II orthosteric antagonists hasbeen shown to enhance signaling by growth factors such as brain derivedneurotrophic factor (BDNF) (Koike et al, Behavioural Brain Research238:48-52, 2013). Since BDNF and other growth factors have been shown tobe critically involved in mediating synaptic plasticity, this mechanismis likely to contribute to both antidepressant and procognitiveproperties of these compounds. Inhibition of mGluRs of the group-IIreceptor family is therefore considered to represent a potentialtherapeutic mechanism for neurological disorders, including depressionand cognitive or memory dysfunction.

DESCRIPTION OF THE INVENTION

The present invention is directed to6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one derivatives of Formula (I)

and stereoisomeric forms thereof, wherein

R¹ is phenyl or 2-pyridinyl, each optionally substituted with one ormore substituents each independently selected from the group consistingof halo, C₁₋₄alkyl, monohalo-C₁₋₄alkyl, polyhalo-C₁₋₄alkyl,—C₁₋₄alkyl-OH, —CN, —C₁₋₄alkyl-O—C₁₋₄alkyl, C₃₋₇cycloalkyl,—O—C₁₋₄alkyl, monohalo-C₁₋₄alkyloxy, polyhalo-C₁₋₄alkyloxy, SF₅,C₁₋₄alkylthio, monohalo-C₁₋₄alkylthio and polyhalo-C₁₋₄alkylthio;

R² is selected from the group consisting of hydrogen; C₁₋₄alkyl;C₃₋₇cycloalkyl; Het¹; Aryl; —C(O)R⁵; —C(O)Het²; Het²; and C₁₋₄alkylsubstituted with one or more substituents each independently selectedfrom the group consisting of halo, C₃₋₇cycloalkyl, Aryl, Het¹ and Het²;wherein

R⁵ is selected from the group consisting of hydrogen, C₁₋₄alkyl andC₃₋₇cycloalkyl;

Aryl is phenyl optionally substituted with one or more substituents eachindependently selected from the group consisting of halo, C₁₋₄alkyl,—C₁₋₄alkyl-OH, monohalo-C₁₋₄alkyl, polyhalo-C₁₋₄alkyl, —CN,—O—C₁₋₄alkyl, —OH, —C₁₋₄alkyl-O—C₁₋₄alkyl, —NR′R″, —NHC(O)C₁₋₄alkyl,—C(O)NR′R″, —C(O)NH[C(O)C₁₋₄alkyl], —S(O)₂NR′R″, —S(O)₂NH[C(O)C₁₋₄alkyl]and —SO₂—C₁₋₄alkyl;

Het¹ is selected from the group consisting of oxetanyl,tetrahydrofuranyl and tetrahydropyranyl;

Het² is (a) a 6-membered aromatic heterocyclyl substituent selected fromthe group consisting of pyridinyl, pyrimidinyl, pyrazinyl andpyridazinyl, each of which may be optionally substituted with one ormore substituents each independently selected from the group consistingof halo, C₁₋₄alkyl, —C₁₋₄alkyl-OH monohalo-C₁₋₄alkyl,polyhalo-C₁₋₄alkyl, —CN, —O—C₁₋₄alkyl, —OH, —C₁₋₄alkyl-O—C₁₋₄alkyl,—NR′R″, —NHC(O)C₁₋₄alkyl, —C(O)NR′R″, —C(O)NH[C(O)C₁₋₄alkyl],—S(O)₂NR′R″, —S(O)₂NH[C(O)C₁₋₄alkyl] and —SO₂—C₁₋₄alkyl; or

(b) a 5-membered aromatic heterocyclyl selected from the groupconsisting of thiazolyl, oxazolyl, 1H-pyrazolyl and 1H-imidazolyl, eachof which may be optionally substituted with one or more substituentseach independently selected from the group consisting of halo,C₁₋₄alkyl, —C₁₋₄alkyl-OH, monohalo-C₁₋₄alkyl, polyhalo-C₁₋₄alkyl, —CN,—O—C₁₋₄alkyl, —OH, —C₁₋₄alkyl-O—C₁₋₄alkyl, —NR′R″, —NHC(O)C₁₋₄alkyl,—C(O)NR′R″, —C(O)NH[C(O)C₁₋₄alkyl], —S(O)₂NR′R″, —S(O)₂NH[C(O)C₁₋₄alkyl]and —SO₂—C₁₋₄alkyl;

R′ and R″ are each independently selected from hydrogen and C₁₋₄alkyl;and

R³ is selected from hydrogen and C₁₋₄alkyl;

R⁴ is selected from the group consisting of hydrogen, C₁₋₄alkyl,monohalo-C₁₋₄alkyl, polyhalo-C₁₋₄alkyl, —C₁₋₄alkyl-O—C₁₋₄alkyl and—C₁₋₄alkyl-OH;

and the N-oxides and the pharmaceutically acceptable salts and thesolvates thereof.

The present invention also relates to a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of Formula(I) and a pharmaceutically acceptable carrier or excipient.

Additionally, the invention relates to a compound of Formula (I) for useas a medicament, and to a compound of Formula (I) for use in thetreatment or in the prevention of central nervous system conditions ordiseases selected from mood disorders; delirium, dementia, amnestic andother cognitive disorders; disorders usually first diagnosed in infancy,childhood or adolescence; substance-related disorders; schizophrenia andother psychotic disorders; somatoform disorders; and hypersomnic sleepdisorder.

The invention also relates to the use of a compound of Formula (I) incombination with an additional pharmaceutical agent for use in thetreatment or prevention of central nervous system conditions or diseasesselected from mood disorders; delirium, dementia, amnestic and othercognitive disorders; disorders usually first diagnosed in infancy,childhood or adolescence; substance-related disorders; schizophrenia andother psychotic disorders; somatoform disorders; and hypersomnic sleepdisorder.

Furthermore, the invention relates to a process for preparing apharmaceutical composition according to the invention, characterized inthat a pharmaceutically acceptable carrier is intimately mixed with atherapeutically effective amount of a compound of Formula (I).

The invention also relates to a method of treating or preventing acentral nervous system disorder selected from mood disorders; delirium,dementia, amnestic and other cognitive disorders; disorders usuallyfirst diagnosed in infancy, childhood or adolescence; substance-relateddisorders; schizophrenia and other psychotic disorders; somatoformdisorders; and hypersomnic sleep disorder, comprising administering to asubject in need thereof, a therapeutically effective amount of acompound of Formula (I) or a therapeutically effective amount of apharmaceutical composition according to the invention.

The invention also relates to a product comprising a compound of Formula(I) and an additional pharmaceutical agent, as a combined preparationfor simultaneous, separate or sequential use in the treatment orprevention of central nervous system conditions or diseases selectedfrom mood disorders; delirium, dementia, amnestic and other cognitivedisorders; disorders usually first diagnosed in infancy, childhood oradolescence; substance-related disorders; schizophrenia and otherpsychotic disorders; somatoform disorders; and hypersomnic sleepdisorder.

The invention also relates to6,7-dihydropyrazolo[1,5-a]pyrazine-4(5H)-one derivatives designed tobind irreversibly to the mGluR2 receptor.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates in particular to compounds of Formula (I)as defined hereinabove, and stereoisomeric forms thereof, wherein

R¹ is phenyl or 2-pyridinyl, each optionally substituted with one ormore substituents each independently selected from the group consistingof halo, C₁₋₄alkyl, monohalo-C₁₋₄alkyl, polyhalo-C₁₋₄alkyl,—C₁₋₄alkyl-OH, —CN, —C₁₋₄alkyl-O—C₁₋₄alkyl, C₃₋₇cycloalkyl,—O—C₁₋₄alkyl, monohalo-C₁₋₄alkyloxy, polyhalo-C₁₋₄alkyloxy, SF₅,C₁₋₄alkylthio, monohalo-C₁₋₄alkylthio and polyhalo-C₁₋₄alkylthio;

R² is selected from the group consisting of hydrogen; C₁₋₄alkyl;C₃₋₇cycloalkyl; Het¹; Aryl; —C(O)R⁵; —C(O)Het²; Het²; and C₁₋₄alkylsubstituted with one or more substituents each independently selectedfrom the group consisting of C₃₋₇cycloalkyl, Aryl, Het¹ and Het²;wherein

R⁵ is selected from the group consisting of hydrogen, C₁₋₄alkyl andC₃₋₇cycloalkyl;

Aryl is phenyl optionally substituted with one or more substituents eachindependently selected from the group consisting of halo, C₁₋₄alkyl,—O—C₁₋₄alkyl, —C₁₋₄alkyl-O—C₁₋₄alkyl and —SO₂—C₁₋₄alkyl;

Het¹ is selected from the group consisting of oxetanyl,tetrahydrofuranyl and tetrahydropyranyl;

Het² is (a) a 6-membered aromatic heterocyclyl substituent selected fromthe group consisting of pyridinyl, pyrimidinyl, pyrazinyl andpyridazinyl, each of which may be optionally substituted with one ormore substituents each independently selected from the group consistingof halo, C₁₋₄alkyl, —CN, —OH, —O—C₁₋₄alkyl, —C(O)NR′R″ and —NR′R″; or

(b) a 5-membered aromatic heterocyclyl selected from the groupconsisting of thiazolyl, oxazolyl, 1H-pyrazolyl and 1H-imidazolyl, eachof which may be optionally substituted with one or more substituentseach independently selected from the group consisting of halo,C₁₋₄alkyl, —CN, —OH, —O—C₁₋₄alkyl, —C(O)NR′R″ and —NR′R″;

R′ and R″ are each independently selected from hydrogen and C₁₋₄alkyl;and

R³ is selected from hydrogen and C₁₋₄alkyl;

R⁴ is selected from the group consisting of hydrogen, C₁₋₄alkyl,monohalo-C₁₋₄alkyl, polyhalo-C₁₋₄alkyl, —C₁₋₄alkyl-O—C₁₋₄alkyl and—C₁₋₄alkyl-OH;

and the N-oxides and the pharmaceutically acceptable salts and thesolvates thereof.

In an additional embodiment, the present invention relates to compoundsof Formula (I) as defined hereinabove and stereoisomeric forms thereof,wherein

R¹ is phenyl or 2-pyridinyl, each optionally substituted with one or twosubstituents each independently selected from the group consisting ofhalo, C₁₋₄alkyl, monohalo-C₁₋₄alkyl, polyhalo-C₁₋₄alkyl, —CN,—C₁₋₄alkyl-O—C₁₋₄alkyl, —O—C₁₋₄alkyl and monohalo-C₁₋₄alkyloxy andpolyhalo-C₁₋₄alkyloxy;

R² is selected from the group consisting of hydrogen; C₁₋₄alkyl;C₃₋₇cycloalkyl;

Aryl; —C(O)R⁵; —C(O)Het²; Het²; and C₁₋₄alkyl substituted with one ormore substituents each independently selected from the group consistingof C₃₋₇cycloalkyl, Aryl, Het¹ and Het²; wherein

R⁵ is selected from the group consisting of hydrogen, C₁₋₄alkyl andC₃₋₇cycloalkyl;

Aryl is phenyl optionally substituted with a substituent selected fromthe group consisting of halo, C₁₋₄alkyl, —O—C₁₋₄alkyl and—SO₂—C₁₋₄alkyl;

Het¹ is selected from the group consisting of oxetanyl,tetrahydrofuranyl and tetrahydropyranyl;

Het² is (a) a 6-membered aromatic heterocyclyl substituent selected fromthe group consisting of pyridinyl, pyrimidinyl and pyrazinyl, each ofwhich may be optionally substituted with one or two substituents eachindependently selected from the group consisting of halo, C₁₋₄alkyl,—O—C₁₋₄alkyl and —NR′R″; or

(b) a 5-membered aromatic heterocyclyl selected from the groupconsisting of thiazolyl, oxazolyl and 1H-imidazolyl, each of which maybe optionally substituted with a C₁₋₄alkyl substituent;

R′ and R″ are each independently selected from hydrogen and C₁₋₄alkyl;and

R³ is hydrogen;

R⁴ is selected from the group consisting of hydrogen, C₁₋₄alkyl and—C₁₋₄alkyl-O—C₁₋₄alkyl;

and the N-oxides and the pharmaceutically acceptable salts and thesolvates thereof.

In a further embodiment, the present invention relates to compounds ofFormula (I) as defined hereinabove and stereoisomeric forms thereof,wherein

R¹ is phenyl or 2-pyridinyl, each optionally substituted with one or twosubstituents each independently selected from the group consisting ofhalo, C₁₋₄alkyl, polyhalo-C₁₋₄alkyl, —C₁₋₄alkyl-O—C₁₋₄alkyl,—O—C₁₋₄alkyl and polyhalo-C₁₋₄alkyloxy;

R² is selected from the group consisting of Aryl; and Het²; wherein

Aryl is phenyl optionally substituted with a halo substituent;

Het¹ is selected from the group consisting of oxetanyl,tetrahydrofuranyl and tetrahydropyranyl;

Het² is (a) a 6-membered aromatic heterocyclyl substituent selected fromthe group consisting of pyridinyl, pyrimidinyl and pyrazinyl, each ofwhich may be optionally substituted with one or two substituents eachindependently selected from the group consisting of halo, C₁₋₄alkyl,—O—C₁₋₄alkyl and NR′R″; or

(b) a 5-membered aromatic heterocyclyl selected from the groupconsisting of thiazolyl, 1,2-oxazolyl, 1,3-oxazolyl and 1H-imidazolyl,each of which may be optionally substituted with a C₁₋₄alkylsubstituent;

R′ and R″ are each hydrogen; and

R³ is hydrogen;

R⁴ is selected from the group consisting of hydrogen, C₁₋₄alkyl and—C₁₋₄alkyl-O—C₁₋₄ alkyl;

and the N-oxides and the pharmaceutically acceptable salts and thesolvates thereof.

In a further embodiment, the present invention relates to compounds ofFormula (I) as defined hereinabove and stereoisomeric forms thereof,wherein

R¹ is phenyl or 2-pyridinyl, each optionally substituted with one or twosubstituents each independently selected from the group consisting ofhalo, C₁₋₄alkyl, polyhalo-C₁₋₄alkyl, —O—C₁₋₄alkyl andpolyhalo-C₁₋₄alkyloxy;

R² is selected from the group consisting of Aryl; and Het²; wherein

Aryl is phenyl optionally substituted with a halo substituent;

Het¹ is selected from the group consisting of oxetanyl,tetrahydrofuranyl and tetrahydropyranyl;

Het² is (a) pyridinyl or pyrazinyl, each of which may be optionallysubstituted with one or two substituents each independently selectedfrom the group consisting of halo, C₁₋₄alkyl, —O—C₁₋₄alkyl and NR′R″; or(b) a thiazolyl;

R′ and R″ are each hydrogen; and

>CR³R⁴ is selected from >CH(CH₃) and >CH(CH₂OCH₃);

and the N-oxides and the pharmaceutically acceptable salts and thesolvates thereof.

In a further embodiment, the present invention relates to compounds ofFormula (I) as defined hereinabove and stereoisomeric forms thereof,wherein

R¹ is phenyl substituted with one or two substituents each independentlyselected from the group consisting of halo, C₁₋₄alkyl,polyhalo-C₁₋₄alkyl and —O—C₁₋₄alkyl;

R² is Het²; wherein

Het² is pyridinyl or pyrazinyl, each of which may be optionallysubstituted with one or two substituents each independently selectedfrom the group consisting of halo, C₁₋₄alkyl, —O—C₁₋₄alkyl and NH₂;

>CR³R⁴ is >CH(CH₃);

and the N-oxides and the pharmaceutically acceptable salts and thesolvates thereof.

In a further embodiment, the present invention relates to compounds ofFormula (I) as defined herein wherein R³ is hydrogen and R⁴ is asubstituent different from hydrogen having a configuration as depictedin the Formula (I′) below, wherein the6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one core, R¹ and R² are in theplane of the drawing and R⁴ is projected above the plane of the drawing(bond shown with a bold wedge) and the rest of variables are as definedin Formula (I) herein

In a yet further embodiment, the present invention relates to compoundsof Formula (I) as defined herein wherein R⁴ is hydrogen and R³ is asubstituent different from hydrogen, for example a C₁₋₄alkyl substituenthaving a configuration as depicted in the Formula (I″) below, whereinthe 6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one core, R¹ and R² are inthe plane of the drawing and R³ is projected above the plane of thedrawing (bond shown with a bold wedge), and the rest of variables are asdefined in Formula (I) herein

Specific compounds according to the invention include:

-   (7S)-7-methyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)—N-(6-fluoro-3-pyridyl)-7-methyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)—N-(6-amino-3-pyridyl)-7-methyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)—N-formyl-7-methyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-7-methyl-N-(2-methyl-4-pyridyl)-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-7-methyl-N-(2-methylpyridine-4-carbonyl)-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)—N,7-dimethyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-7-methyl-4-oxo-N-tetrahydropyran-4-yl-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-7-methyl-4-oxo-N-phenyl-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)—N-tert-butyl-7-methyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)—N-cyclohexyl-7-methyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)—N-benzyl-7-methyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)—N-[(6-amino-3-pyridyl)methyl]-7-methyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)—N-(4-fluorophenyl)-7-methyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)—N-(cyclopentylmethyl)-7-methyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-7-methyl-4-oxo-N-(2-pyridyl)-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-7-methyl-N-(2-methylpyrimidin-5-yl)-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-7-methyl-N-[(2-methyl-4-pyridyl)methyl]-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)—N-(cyclopropylmethyl)-7-methyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-(3,4-dichlorophenyl)-N-(6-fluoro-3-pyridyl)-7-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-7-methyl-N-(3-methylsulfonylphenyl)-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-7-methyl-N-(4-methylsulfonylphenyl)-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7*S)—N-(1-cyclopropylethyl)-7-methyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-(3,4-dichlorophenyl)-7-methyl-N-(2-methyl-4-pyridyl)-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-(4-chlorophenyl)-7-methyl-N-(2-methyl-4-pyridyl)-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-7-methyl-N-(2-methyl-4-pyridyl)-5-[3-methyl-4-(trifluoromethyl)phenyl]-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-[3-cyano-4-(trifluoromethyl)phenyl]-7-methyl-N-(2-methyl-4-pyridyl)-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-[3-methoxy-4-(trifluoromethyl)phenyl]-7-methyl-N-(2-methyl-4-pyridyl)-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-7-methyl-N-(2-methyl-4-pyridyl)-4-oxo-5-[5-(trifluoromethyl)-2-pyridyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-[3-fluoro-4-(trifluoromethyl)phenyl]-7-methyl-N-(2-methyl-4-pyridyl)-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)—N-(cyclobutylmethyl)-7-methyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-7-methyl-4-oxo-N-(tetrahydrofuran-2-ylmethyl)-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-7-methyl-4-oxo-N-(tetrahydropyran-4-ylmethyl)-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)—N-(2-methoxyphenyl)-5-[6-methoxy-5-(trifluoromethyl)-2-pyridyl]-7-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-(5-chloro-6-methoxy-2-pyridyl)-7-methyl-4-oxo-N-phenyl-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)—N-(3-methoxyphenyl)-5-[6-methoxy-5-(trifluoromethyl)-2-pyridyl]-7-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-[6-methoxy-5-(trifluoromethyl)-2-pyridyl]-7-methyl-4-oxo-N-phenyl-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)—N-(4-methoxyphenyl)-5-[6-methoxy-5-(trifluoromethyl)-2-pyridyl]-7-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-7-methyl-4-oxo-N-(tetrahydrofuran-3-ylmethyl)-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-7-methyl-4-oxo-N-(4-pyridyl)-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)—N-(5-methoxy-3-pyridyl)-7-methyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-7-methyl-4-oxo-N-(3-pyridyl)-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-7-methyl-N-(2-methyl-3-pyridyl)-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)—N-(3-fluoro-4-pyridyl)-7-methyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-7-methyl-N-(5-methyl-3-pyridyl)-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-7-methyl-N-(4-methyl-3-pyridyl)-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-[3-(methoxymethyl)-4-(trifluoromethyl)phenyl]-7-methyl-N-(2-methyl-4-pyridyl)-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)—N-(5-fluoro-3-pyridyl)-7-methyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-[3-chloro-4-(difluoromethyl)phenyl]-7-methyl-N-(2-methyl-4-pyridyl)-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)—N-(6-methoxy-2-pyridyl)-7-methyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)—N-(cyclobutanecarbonyl)-7-methyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)—N-(5-fluoro-2-pyridyl)-7-methyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-7-methyl-4-oxo-N-pyrimidin-2-yl-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)—N-(5-methoxy-2-pyridyl)-7-methyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-[3-(methoxymethyl)-4-(trifluoromethyl)phenyl]-7-methyl-4-oxo-N-(2-pyridyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   7-(methoxymethyl)-N-(2-methyl-4-pyridyl)-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)—N-(3-fluoro-2-pyridyl)-7-methyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)—N-(3-methoxy-2-pyridyl)-7-methyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-(3,4-dichlorophenyl)-7-methyl-4-oxo-N-(2-pyridyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-7-methyl-5-[3-methyl-4-(trifluoromethyl)phenyl]-4-oxo-N-(2-pyridyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-7-methyl-N-(oxetan-3-yl)-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)—N-cyclobutyl-7-methyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7*R)-7-(methoxymethyl)-N-(2-methyl-4-pyridyl)-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7*S)-7-(methoxymethyl)-N-(2-methyl-4-pyridyl)-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-[3-chloro-4-(trifluoromethyl)phenyl]-7-methyl-4-oxo-N-(2-pyridyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)—N-(2,6-dimethyl-4-pyridyl)-7-methyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-7-methyl-4-oxo-N-pyrazin-2-yl-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-[3-fluoro-4-(trifluoromethyl)phenyl]-7-methyl-4-oxo-N-(2-pyridyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)—N-acetyl-7-methyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-[4-chloro-3-(difluoromethoxy)phenyl]-7-methyl-N-(2-methyl-4-pyridyl)-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-7-methyl-N-(2-methyl-4-pyridyl)-4-oxo-5-phenyl-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-7-methyl-N-oxazol-2-yl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-[3-(fluoromethyl)-4-(trifluoromethyl)phenyl]-7-methyl-4-oxo-N-(3-pyridyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-[3-(fluoromethyl)-4-(trifluoromethyl)phenyl]-7-methyl-N-(2-methyl-4-pyridyl)-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-7-methyl-4-oxo-N-thiazol-2-yl-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-7-methyl-4-oxo-N-pyrimidin-4-yl-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-7-methyl-N-(6-methyl-2-pyridyl)-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)—N-(1H-imidazol-2-yl)-7-methyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)—N-(3-methoxy-4-pyridyl)-7-methyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-[3-(fluoromethyl)-4-(trifluoromethyl)phenyl]-7-methyl-4-oxo-N-(4-pyridyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-[3-chloro-4-(trifluoromethyl)phenyl]-7-methyl-4-oxo-N-(3-pyridyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-7-methyl-N-(3-methyl-2-pyridyl)-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-[3-chloro-4-(trifluoromethyl)phenyl]-7-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-(3,4-dichlorophenyl)-N-(5-fluoro-2-pyridyl)-7-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-(3,4-dichlorophenyl)-7-methyl-4-oxo-N-(3-pyridyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-7-methyl-N-(4-methyl-2-pyridyl)-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-7-methyl-N-(5-methyl-3-pyridyl)-5-[3-methyl-4-(trifluoromethyl)phenyl]-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-7-methyl-5-[3-methyl-4-(trifluoromethyl)phenyl]-4-oxo-N-(3-pyridyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-[3-chloro-4-(trifluoromethyl)phenyl]-7-methyl-4-oxo-N-pyrazin-2-yl-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-7-methyl-5-[3-methyl-4-(trifluoromethyl)phenyl]-4-oxo-N-pyrazin-2-yl-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-[3-chloro-4-(trifluoromethyl)phenyl]-7-methyl-N-(2-methyl-4-pyridyl)-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-7-methyl-5-[3-methyl-4-(trifluoromethyl)phenyl]-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)—N-(5-fluoro-4-methyl-3-pyridyl)-7-methyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-[3-chloro-4-(trifluoromethyl)phenyl]-N-(5-fluoro-4-methyl-3-pyridyl)-7-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-(3,4-dichlorophenyl)-7-methyl-4-oxo-N-pyrazin-2-yl-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-(3,4-dichlorophenyl)-N-(2,6-dimethyl-4-pyridyl)-7-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-[3-chloro-4-(trifluoromethyl)phenyl]-N-(2,6-dimethyl-4-pyridyl)-7-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-[3-chloro-4-(trifluoromethyl)phenyl]-N-(5-fluoro-2-pyridyl)-7-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-[3-chloro-4-(trifluoromethyl)phenyl]-N-(4,5-dimethyl-3-pyridyl)-7-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)—N-(5-methoxy-4-methyl-3-pyridyl)-7-methyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-[3-chloro-4-(trifluoromethyl)phenyl]-N-(5-methoxy-4-methyl-3-pyridyl)-7-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)—N-(2,6-dimethyl-4-pyridyl)-7-methyl-5-[3-methyl-4-(trifluoromethyl)phenyl]-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)—N-(5-fluoro-2-pyridyl)-7-methyl-5-[3-methyl-4-(trifluoromethyl)phenyl]-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-(3,4-dichlorophenyl)-7-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-(3,4-dichlorophenyl)-7-methyl-N-(5-methyl-3-pyridyl)-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)—N-(5-fluoro-3-pyridyl)-7-methyl-5-[3-methyl-4-(trifluoromethyl)phenyl]-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)—N-(5-methoxy-3-pyridyl)-7-methyl-5-[3-methyl-4-(trifluoromethyl)phenyl]-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-(4-chlorophenyl)-7-methyl-4-oxo-N-(3-pyridyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-[3-fluoro-4-(trifluoromethyl)phenyl]-7-methyl-4-oxo-N-(3-pyridyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)—N-(5-fluoro-2-pyridyl)-5-[3-methoxy-4-(trifluoromethyl)phenyl]-7-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-(3,4-dichlorophenyl)-N-(5-methoxy-3-pyridyl)-7-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-7-methyl-N-(4-methyl-3-pyridyl)-5-[3-methyl-4-(trifluoromethyl)phenyl]-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-[3-methoxy-4-(trifluoromethyl)phenyl]-7-methyl-N-(4-methyl-3-pyridyl)-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)—N-(5-fluoro-3-pyridyl)-5-[3-methoxy-4-(trifluoromethyl)phenyl]-7-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-(3,4-dichlorophenyl)-N-(5-fluoro-3-pyridyl)-7-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)—N-(5-fluoro-2-pyridyl)-5-[3-fluoro-4-(trifluoromethyl)phenyl]-7-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-(3,4-dichlorophenyl)-7-methyl-N-(4-methyl-3-pyridyl)-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-[3-methoxy-4-(trifluoromethyl)phenyl]-7-methyl-N-(5-methyl-3-pyridyl)-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-[3-chloro-4-(trifluoromethyl)phenyl]-7-methyl-N-(3-methylisoxazol-5-yl)-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)—N-(5-methoxy-3-pyridyl)-5-[3-methoxy-4-(trifluoromethyl)phenyl]-7-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-[3-fluoro-4-(trifluoromethyl)phenyl]-7-methyl-4-oxo-N-pyrazin-2-yl-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-[3-chloro-4-(trifluoromethyl)phenyl]-N-(5-fluoro-3-pyridyl)-7-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-[3-methoxy-4-(trifluoromethyl)phenyl]-7-methyl-4-oxo-N-pyrazin-2-yl-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)—N-(5-fluoro-3-pyridyl)-5-[3-fluoro-4-(trifluoromethyl)phenyl]-7-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-[3-methoxy-4-(trifluoromethyl)phenyl]-7-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)—N-(5-fluoro-4-methyl-3-pyridyl)-5-[3-fluoro-4-(trifluoromethyl)phenyl]-7-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)—N-(5-fluoro-4-methyl-3-pyridyl)-7-methyl-5-[3-methyl-4-(trifluoromethyl)phenyl]-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-(3,4-dichlorophenyl)-N-(5-fluoro-4-methyl-3-pyridyl)-7-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-(4-chlorophenyl)-N-(5-fluoro-4-methyl-3-pyridyl)-7-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-(4-chloro-3-methyl-phenyl)-N-(5-fluoro-4-methyl-3-pyridyl)-7-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)—N-(2,6-dimethyl-4-pyridyl)-5-[3-methoxy-4-(trifluoromethyl)phenyl]-7-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-[3-fluoro-4-(trifluoromethyl)phenyl]-7-methyl-N-(5-methyl-3-pyridyl)-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-[3-chloro-4-(trifluoromethyl)phenyl]-N-(5-methoxy-3-pyridyl)-7-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-7-methyl-N-(6-methylpyrazin-2-yl)-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-(4-chlorophenyl)-7-methyl-N-(4-methyl-3-pyridyl)-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)—N-(2,6-dimethyl-4-pyridyl)-5-[3-fluoro-4-(trifluoromethyl)phenyl]-7-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-[3-chloro-4-(trifluoromethyl)phenyl]-7-methyl-N-(4-methyl-3-pyridyl)-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-(4-chloro-3-methyl-phenyl)-7-methyl-N-(4-methyl-3-pyridyl)-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-(4-chloro-3-methyl-phenyl)-N-(5-fluoro-3-pyridyl)-7-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-[3-chloro-4-(trifluoromethyl)phenyl]-7-methyl-N-(5-methyl-3-pyridyl)-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-(4-chlorophenyl)-N-(5-fluoro-3-pyridyl)-7-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-[3-fluoro-4-(trifluoromethyl)phenyl]-7-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-[3-fluoro-4-(trifluoromethyl)phenyl]-7-methyl-N-(4-methyl-3-pyridyl)-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-(4-chlorophenyl)-7-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   7-(methoxymethyl)-4-oxo-N-pyrazin-2-yl-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-(4-chlorophenyl)-7-methyl-4-oxo-N-pyrazin-2-yl-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-(4-chloro-3-methyl-phenyl)-7-methyl-4-oxo-N-pyrazin-2-yl-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-(4-chloro-3-methyl-phenyl)-N-(2,6-dimethyl-4-pyridyl)-7-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7R*)-7-(methoxymethyl)-4-oxo-N-(3-pyridyl)-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S*)-7-(methoxymethyl)-4-oxo-N-(3-pyridyl)-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7R*)-5-[3-chloro-4-(trifluoromethyl)phenyl]-7-(methoxymethyl)-4-oxo-N-(3-pyridyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S*)-5-[3-chloro-4-(trifluoromethyl)phenyl]-7-(methoxymethyl)-4-oxo-N-(3-pyridyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7R*)-7-(methoxymethyl)-4-oxo-N-pyrazin-2-yl-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S*)-7-(methoxymethyl)-4-oxo-N-pyrazin-2-yl-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   4-oxo-N-(3-pyridyl)-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-[3-chloro-4-(trifluoromethoxy)phenyl]-7-methyl-4-oxo-N-(3-pyridyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)—N-[2-(fluoromethyl)-4-pyridyl]-7-methyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)—N-[2-(hydroxymethyl)-4-pyridyl]-7-methyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)—N-[2-(methoxymethyl)-4-pyridyl]-7-methyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)—N-[5-(hydroxymethyl)-3-pyridyl]-7-methyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)—N-[4-(hydroxymethyl)-3-pyridyl]-7-methyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-(3,4-dichlorophenyl)-N-(6-fluoropyrazin-2-yl)-7-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)—N-(6-fluoropyrazin-2-yl)-7-methyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   5-[3-chloro-4-(trifluoromethyl)phenyl]-7-(methoxymethyl)-4-oxo-N-(3-pyridyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   7-(methoxymethyl)-4-oxo-N-(3-pyridyl)-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   (7S)-5-(4-chloro-3-methyl-phenyl)-7-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide;-   4-[[(7S)-7-methyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carbonyl]amino]benzenesulfonyl    fluoride;

and the pharmaceutically acceptable salts and solvates of suchcompounds.

Particular compounds according to the invention include:

-   (7S)—N-(5-fluoro-3-pyridyl)-7-methyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide    hydrochloride salt;-   (7S)—N-(3-fluoro-2-pyridyl)-7-methyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide    hydrochloride salt;-   (7S)-5-[3-chloro-4-(trifluoromethyl)phenyl]-7-methyl-N-(4-methyl-3-pyridyl)-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide    hydrochloride salt.

The present invention further relates to derivatives designed to bindirreversibly to the mGluR2 receptor, in particular to the allostericpocket thereof.

In an embodiment, these compounds have the formula (I-a)

and stereoisomeric forms thereof, wherein

R¹ is phenyl or 2-pyridinyl, each optionally substituted with one ormore substituents each independently selected from the group consistingof halo, C₁₋₄alkyl, monohalo-C₁₋₄alkyl, polyhalo-C₁₋₄alkyl,—C₁₋₄alkyl-OH, —CN, —C₁₋₄alkyl-O—C₁₋₄alkyl, C₃₋₇cycloalkyl,—O—C₁₋₄alkyl, monohalo-C₁₋₄alkyloxy, polyhalo-C₁₋₄alkyloxy, SF₅,C₁₋₄alkylthio, monohalo-C₁₋₄alkylthio and polyhalo-C₁₋₄alkylthio;

R² is phenyl substituted with —S(O)₂F;

R³ is selected from hydrogen and C₁₋₄alkyl;

R⁴ is selected from the group consisting of hydrogen, C₁₋₄alkyl,monohalo-C₁₋₄alkyl, polyhalo-C₁₋₄alkyl, —C₁₋₄alkyl-O—C₁₋₄alkyl and—C₁₋₄alkyl-OH;

and the N-oxides and the pharmaceutically acceptable salts and thesolvates thereof.

The names of the compounds of the present invention were generatedaccording to the nomenclature rules agreed upon by the InternationalUnion of Pure and Applied Chemistry (IUPAC) generated by AccelrysDirect, Revision 8.0 SP1 (Microsoft Windows 64-bit Oraclell)(8.0.100.4), OpenEye:1.2.0. In case of tautomeric forms, the name of thedepicted tautomeric form of the structure was generated. However itshould be clear that the other non-depicted tautomeric form is alsoincluded within the scope of the present invention.

Definitions

The notation “C₁₋₄alkyl” as used herein alone or as part of anothergroup, defines a saturated, straight or branched, hydrocarbon radicalhaving, unless otherwise stated, from 1 to 4 carbon atoms, such asmethyl, ethyl, 1-propyl, 1-methylethyl, butyl, 1-methyl-propyl,2-methyl-1-propyl, 1,1-dimethylethyl and the like. The notation“—C₁₋₄alkyl-OH” as used herein alone or as part of another group, refersto C₁₋₄alkyl as defined before, substituted with one OH group at anyavailable carbon atom.

The notation “halogen” or “halo” as used herein alone or as part ofanother group, refers to fluoro, chloro, bromo or iodo, with fluoro orchloro being preferred.

The notation “monohalo-C₁₋₄alkyl, polyhalo-C₁₋₄alkyl” as used hereinalone or as part of another group, refers to C₁₋₄alkyl as definedbefore, substituted with 1, 2, 3 or where possible with more halo atomsas defined before

The notation “C₃₋₇cycloalkyl” as used herein refers to a saturated,cyclic hydrocarbon radical having from 3 to 7 carbon atoms, such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Aparticular C₃₋₇cycloalkyl group is cyclopropyl.

The N-oxide forms of the compounds according to Formula (I) are meant tocomprise those compounds of Formula (I) wherein one or several nitrogenatoms are oxidized to the so called N-oxide, particularly those N-oxideswherein a nitrogen atom in a pyridinyl radical is oxidized. N-oxides canbe formed following procedures known to the skilled person. TheN-oxidation reaction may generally be carried out by reacting thestarting material of Formula (I) with an appropriate organic orinorganic peroxide. Appropriate inorganic peroxides comprise, forexample, hydrogen peroxide, alkali metal or alkaline metal peroxides,e.g. sodium peroxide, potassium peroxide/appropriate organic peroxidesmay comprise peroxy acids such as, for example, benzenecarboperoxoicacid or halo substituted benzenecarboperoxoic acid, e.g.3-chloroperoxybenzoic acid (or 3-chloroperbenzoic acid), peroxoalkanoicacids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. tert-butylhydroperoxide. Suitable solvents, are for example, water, loweralkanols, e.g. ethanol and the like, hydrocarbons, e.g. toluene,ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g.dichloromethane, and mixtures of such solvents.

Whenever the term “substituted” is used in the present invention, it ismeant, unless otherwise is indicated or is clear from the context, toindicate that one or more hydrogens, preferably from 1 to 3 hydrogens,more preferably from 1 to 2 hydrogens, more preferably 1 hydrogen, onthe atom or radical indicated in the expression using “substituted” arereplaced with a selection from the indicated group, provided that thenormal valency is not exceeded, and that the substitution results in achemically stable compound, i.e. a compound that is sufficiently robustto survive isolation to a useful degree of purity from a reactionmixture, and formulation into a therapeutic agent.

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who is or has been the object oftreatment, observation or experiment.

The term “therapeutically effective amount” as used herein, means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thedisease or disorder being treated.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.

It will be appreciated that some of the compounds of Formula (I) andtheir pharmaceutically acceptable addition salts and solvates thereofmay contain one or more centres of chirality and exist as stereoisomericforms.

The term “compounds of the invention” as used herein, is meant toinclude the compounds of Formula (I), and the salts and solvatesthereof.

As used herein, any chemical formula with bonds shown only as solidlines and not as solid wedged or hashed wedged bonds, or otherwiseindicated as having a particular configuration (e.g. R, S) around one ormore atoms, contemplates each possible stereoisomer, or mixture of twoor more stereoisomers.

Hereinbefore and hereinafter, the term “compound of Formula (I)” ismeant to include the stereoisomers thereof and the tautomeric formsthereof.

The terms “stereoisomers”, “stereoisomeric forms” or “stereochemicallyisomeric forms” hereinbefore or hereinafter are used interchangeably.

The invention includes all stereoisomers of the compounds of theinvention either as a pure stereoisomer or as a mixture of two or morestereoisomers.

Enantiomers are stereoisomers that are non-superimposable mirror imagesof each other. A 1:1 mixture of a pair of enantiomers is a racemate orracemic mixture.

Diastereomers (or diastereoisomers) are stereoisomers that are notenantiomers, i.e. they are not related as mirror images. If a compoundcontains a double bond, the substituents may be in the E or the Zconfiguration.

Substituents on bivalent cyclic (partially) saturated radicals may haveeither the cis- or trans-configuration; for example if a compoundcontains a disubstituted cycloalkyl group, the substituents may be inthe cis or trans configuration.

Therefore, the invention includes enantiomers, diastereomers, racemates,E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof,whenever chemically possible.

The meaning of all those terms, i.e. enantiomers, diastereomers,racemates, E isomers, Z isomers, cis isomers, trans isomers and mixturesthereof are known to the skilled person.

The absolute configuration is specified according to theCahn-Ingold-Prelog system. The configuration at an asymmetric atom isspecified by either R or S. Resolved stereoisomers whose absoluteconfiguration is not known can be designated by (+) or (−) depending onthe direction in which they rotate plane polarized light. For instance,resolved enantiomers whose absolute configuration is not known can bedesignated by (+) or (−) depending on the direction in which they rotateplane polarized light.

When a specific stereoisomer is identified, this means that saidstereoisomer is substantially free, i.e. associated with less than 50%,preferably less than 20%, more preferably less than 10%, even morepreferably less than 5%, in particular less than 2% and most preferablyless than 1%, of the other isomers. Thus, when a compound of Formula (I)is for instance specified as (R), this means that the compound issubstantially free of the (S) isomer; when a compound of Formula (I) isfor instance specified as E, this means that the compound issubstantially free of the Z isomer; when a compound of Formula (I) isfor instance specified as cis, this means that the compound issubstantially free of the trans isomer.

Some of the compounds according to Formula (I) may also exist in theirtautomeric form. Such forms in so far as they may exist, although notexplicitly indicated in the above formula are intended to be includedwithin the scope of the present invention.

It follows that a single compound may exist in both stereisomeric andtautomeric forms.

For therapeutic use, salts of the compounds of Formula (I) are thosewherein the counterion is pharmaceutically acceptable. However, salts ofacids and bases which are non-pharmaceutically acceptable may also finduse, for example, in the preparation or purification of apharmaceutically acceptable compound. All salts, whetherpharmaceutically acceptable or not, are included within the ambit of thepresent invention.

The pharmaceutically acceptable acid and base addition salts asmentioned hereinabove or hereinafter are meant to comprise thetherapeutically active non-toxic acid and base addition salt forms whichthe compounds of Formula (I) are able to form. The pharmaceuticallyacceptable acid addition salts can conveniently be obtained by treatingthe base form with such appropriate acid. Appropriate acids comprise,for example, inorganic acids such as hydrohalic acids, e.g. hydrochloricor hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; ororganic acids such as, for example, acetic, propanoic, hydroxyacetic,lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e.butanedioic acid), maleic, fumaric, malic, tartaric, citric,methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic,cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.Conversely said salt forms can be converted by treatment with anappropriate base into the free base form.

The compounds of Formula (I) containing an acidic proton may also beconverted into their non-toxic metal or amine addition salt forms bytreatment with appropriate organic and inorganic bases. Appropriate basesalt forms comprise, for example, the ammonium salts, the alkali andearth alkaline metal salts, e.g. the lithium, sodium, potassium,magnesium, calcium salts and the like, salts with organic bases, e.g.primary, secondary and tertiary aliphatic and aromatic amines such asmethylamine, ethylamine, propylamine, isopropylamine, the fourbutylamine isomers, dimethylamine, diethylamine, diethanolamine,dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine,piperidine, morpholine, trimethylamine, triethylamine, tripropylamine,quinuclidine, pyridine, quinoline and isoquinoline; the benzathine,N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids suchas, for example, arginine, lysine and the like. Conversely the salt formcan be converted by treatment with acid into the free acid form.

The term solvate comprises the solvent addition forms as well as thesalts thereof, which the compounds of Formula (I) are able to form.Examples of such solvent addition forms are e.g. hydrates, alcoholatesand the like.

In the framework of this application, an element, in particular whenmentioned in relation to a compound according to Formula (I), comprisesall isotopes and isotopic mixtures of this element, either naturallyoccurring or synthetically produced, either with natural abundance or inan isotopically enriched form, for example ²H. Radiolabelled compoundsof Formula (I) may comprise a radioactive isotope selected from thegroup consisting of ³H, ¹¹C, ¹⁴C, ¹⁸F, ¹²²I, ¹²³I, ¹²⁵I, ¹³¹I, ⁷⁵Br,⁷⁶Br, ⁷⁷Br and ⁸²Br. Preferably, the radioactive isotope is selectedfrom the group consisting of ³H, ¹¹C and ¹⁸F.

Preparation

The compounds according to the invention can generally be prepared by asuccession of steps, each of which is known to the skilled person. Inparticular, the compounds can be prepared according to the followingsynthesis methods.

The compounds of Formula (I) may be synthesized in the form of racemicmixtures of enantiomers which can be separated from one anotherfollowing art-known resolution procedures. The racemic compounds ofFormula (I) may be converted into the corresponding diastereomeric saltforms by reaction with a suitable chiral acid. Said diastereomeric saltforms are subsequently separated, for example, by selective orfractional crystallization and the enantiomers are liberated therefromby alkali. An alternative manner of separating the enantiomeric forms ofthe compounds of Formula (I) involves liquid chromatography using achiral stationary phase or chiral supercritical fluid chromatography(SFC). Said pure stereochemically isomeric forms may also be derivedfrom the corresponding pure stereochemically isomeric forms of theappropriate starting materials, provided that the reaction occursstereospecifically. The absolute configuration of compounds of theinvention reported herein was determined by analysis of the racemicmixture by supercritical fluid chromatography (SFC) followed by SFCcomparison of the separate enantiomer(s) which were obtained byasymmetric synthesis, followed by vibrational circular dichroism (VCD)analysis of the particular enantiomer(s).

A. Preparation of the Final Compounds Experimental Procedure 1

Final compounds according to Formula (I-a) can be prepared by a couplingreaction of a compound of Formula (II-a) with a compound of Formula(III), according to conditions known to the skilled person. Suchconditions for example include a suitable coupling agent such asO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDCI) or2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU) in presence of a suitable base such asN,N-diisopropylethylamine (DIPEA), triethylamine (Et₃N) or4-(dimethylamino)pyridine (DMAP) in a suitable solvent such asN,N-dimethylformamide (DMF) or dichloromethane (DCM) under suitablereaction conditions, such as at a convenient temperature, typically roomtemperature (rt), for a period of time to ensure the completion of thereaction. A compound of Formula (III) can be obtained commercially ormade according to procedures known in the art. In Reaction Scheme 1, allvariables are defined as in Formula (I).

Experimental Procedure 2

Alternatively, final compounds according to Formula (I-a) can beprepared by a Goldberg coupling reaction of a compound of Formula (II-b)with an appropriate aryl/heteroaryl halide of Formula (IV) where X is ahalo, according to conditions known to the skilled person. Suchconditions for example include the use of a suitable palladium catalystsystem such as tris(dibenzylideneacetone)dipalladium(0) (Pd₂(dba)₃), inthe presence of a ligand such as4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), in thepresence of a suitable base such as potassium phosphate (K₃PO₄) in asuitable solvent such as tetrahydrofuran (THF), under suitable reactionconditions, such as at a convenient temperature, typically rangingbetween 80° C. and 100° C., in particular 90° C., for a period of timeto ensure the completion of the reaction. A compound of Formula (IV) canbe obtained commercially or made according to procedures known in theart. In Reaction Scheme 2, all variables are defined as in Formula (I).

Alternatively, final compounds according to Formula (I-a) can beprepared by a Goldberg coupling reaction of a compound of Formula (II-b)with an appropriate aryl/heteroaryl halide of Formula (IV) where X is ahalo, according to conditions known to the skilled person. Suchconditions for example include the use of a suitable copper catalystsuch as copper(I) iodide, in the presence of a ligand such as(+/−)-trans-1,2-cyclohexanediamine, in the presence of a suitable basesuch as potassium phosphate (K₃PO₄), with or without an organic basesuch as triethylamine (TEA), in a suitable solvent such as 1,4-dioxane,under suitable reaction conditions, such as at a convenient temperature,typically ranging between 80° C. and 120° C., in particular 100° C., fora period of time to ensure the completion of the reaction. A compound ofFormula (IV) can be obtained commercially or made according toprocedures known in the art. In Reaction Scheme 2, all variables aredefined as in Formula (I).

Experimental Procedure 3

Alternatively, final compounds according to Formula (I-a) can beprepared by a reaction between an activated ester of Formula (II-c) witha compound of Formula (III) according to conditions known to the skilledperson. Such conditions for example include the use of a suitable basesuch as Et₃N and a suitable activating agent such as DMAP in a suitablesolvent such as THF under suitable reaction conditions such as at aconvenient temperature, typically ranging between 60° C. and 80° C., inparticular 70° C., for a period of time to ensure the completion of thereaction. A compound of Formula (III) can be obtained commercially ormade according to procedures known in the art. In Reaction Scheme 3, allvariables are defined as in Formula (I).

Experimental Procedure 4

Alternatively, final compounds according to Formula (I-a) can beprepared by a one pot reaction of carbonylation of a compound of Formula(V) combined with a peptide type coupling reaction with an appropriatecompound of Formula (III), according to conditions known to the skilledperson. Such conditions for example include the use of carbon monoxideand a suitable palladium catalyst system such as palladium(II) acetate,in the presence of a ligand such as 1,1′-bis(diphenylphosphino)ferrocene (dppf), in the presence of a suitable base such as Et₃N in asuitable solvent such as 1,4-dioxane, under suitable reactionconditions, such as at a convenient temperature, typically rangingbetween 80° C. and 100° C., in particular 90° C., for a period of timeto ensure the completion of the reaction. A compound of Formula (III)can be obtained commercially or made according to procedures known inthe art. In Reaction Scheme 4, all variables are defined as in Formula(I).

Experimental Procedure 5

Alternatively, final compounds according to Formula (I-a) can beprepared by a reaction between an ester of Formula (II-d) wherein R^(y)is C₁₋₄alkyl with a compound of Formula (III) according to conditionsknown to the skilled person. Such conditions for example include the useof a suitable Lewis Acid such as trimethylaluminium (AlMe₃) or aGrignard reagent, such as for example isopropylmagnesium chloridelithium chloride complex solution or ethylmagnesium bromide or asuitable base such as lithium bis(trimethylsilyl)amide, in a suitablesolvent such as THF under suitable reaction conditions such as such asat a convenient temperature, typically ranging between 0° C. and 30° C.,for a period of time to ensure the completion of the reaction. Acompound of Formula (III) can be obtained commercially or made accordingto procedures known in the art. In Reaction Scheme 5, all variables aredefined as in Formula (I).

Experimental Procedure 6

Alternatively, final compounds according to Formula (I), wherein R² is—C(O)R⁵ or Het² and wherein R⁵ is as defined hereinbefore excepthydrogen (hereby referred to as substituent R^(2a)), hereby referred toas compounds of Formula (I-b1) can be prepared by a one-step oxidationof a compound of Formula (II-e) according to conditions known to theskilled person. Such conditions for example include the use of asuitable oxidating reagent such as for example Dess-Martin Periodinane®,in a suitable mixture of solvent such as fluorobenzene anddimethylsulfoxide (DMSO) and under suitable reaction conditions such assuch as at a convenient temperature, typically ranging between 80° C.and 100° C., in particular 85° C., for a period of time to ensure thecompletion of the reaction. In Reaction Scheme 6, all variables aredefined as in Formula (I).

Experimental Procedure 7

Alternatively, final compounds according to Formula (I-b1) (as definedin experimental procedure 6) can be prepared by acylation of a compoundof Formula (II-b) with an appropriate acid chloride of Formula (VI)according to conditions known to the skilled person. Such conditions forexample include the use of a suitable base such as for example pyridine,under suitable reaction conditions such as at a convenient temperature,typically ranging between 40° C. and 60° C., in particular 50° C., for aperiod of time to ensure the completion of the reaction. A compound ofFormula (VI) can be obtained commercially or made according toprocedures known in the art. In Reaction Scheme 7, all variables aredefined as in Formula (I).

Experimental Procedure 8

Alternatively, final compounds according to Formula (I) wherein R² is—C(O)R⁵ and wherein R⁵ is hydrogen hereby referred to as compounds ofFormula (I-b2) can be prepared by formylation of a compound of Formula(II-b) with N,N-dimethylformamide dimethyl acetal (DMFDMA) according toconditions known to the skilled person. In Reaction Scheme 8, allvariables are defined as in Formula (I).

Experimental Procedure 9

Alternatively, final compounds according to Formula (I-a) can beprepared by a reaction of deprotection of a compound of Formula (I-a1)according to conditions known to the skilled person. A compound ofFormula (I-a1) can be obtained by removal of the protecting group suchas for example a dimethylpyrrole protecting group in the compound ofFormula (I-a1), in the presence of basic media, such as hydroxylaminehydrochloride and Et₃N in an inert solvent such as a mixture ofethanol/water, under suitable reaction conditions, such as at aconvenient temperature, typically ranging between 80° C. and 120° C., inparticular 100° C., for a period of time to ensure the completion of thereaction. In Reaction Scheme 9, all variables are defined as in Formula(I) and R^(2b) include the residues indicated in the scope as R² as wellas their protected forms.

B. Preparation of the Intermediate Compounds Experimental Procedure 10

Intermediate compounds according to Formula (II-a) can be preparedfollowing art known procedures such as for example a transition metalcatalyzed carbon monoxide insertion reaction of an intermediate compoundof Formula (V) according to conditions known to the skilled person. Suchconditions for example include the use of carbon monoxide and a suitablepalladium catalyst system such as palladium(II) acetate, in the presenceof a ligand such as dppf, in the presence of a suitable base such asEt₃N in a suitable solvent such as 1,4-dioxane and water, under suitablereaction conditions, such as at a convenient temperature, typicallyranging between 70° C. and 90° C., in particular 80° C., for a period oftime to ensure the completion of the reaction. Alternatively, an esterof Formula (II-d) can be saponified to give intermediate compound ofFormula (II-a). The reaction can be performed for example by adding ahydroxide, such as sodium hydroxide (NaOH), to a solution of ester ofFormula (II-d) in a suitable polar solvent such as methanol (MeOH).Heating the reaction mixture can enhance the reaction outcome.Alternatively a nitrile of Formula (II-f) can be hydrolyzed to give anintermediate compound of Formula (II-a). The reaction can be performedfor example by heating a solution of nitrile of Formula (II-f) in asuitable solvent such as an aqueous solution of hydrochloric acid.Heating the reaction mixture can enhance the reaction outcome.

Intermediate compounds according to Formula (II-d) wherein R^(y) isC₁₋₄alkyl can be prepared following art known procedures such as forexample a transition metal catalyzed carbon monoxide insertion reactionof an intermediate compound of Formula (V) according to conditions knownto the skilled person. Such conditions for example include the use ofcarbon monoxide and a suitable palladium catalyst system such aspalladium(II) acetate, in the presence of a ligand such as dppf, in thepresence of a suitable base such as Et₃N in a suitable solvent such as1,4-dioxane and ethanol (EtOH), under suitable reaction conditions, suchas at a convenient temperature, typically ranging between 80° C. and100° C., in particular 95° C., for a period of time to ensure thecompletion of the reaction.

Intermediate compounds according to Formula (II-f) can be preparedfollowing art known procedures such as for example a palladium catalyzedreaction with zinc cyanide of an intermediate of Formula (V). Suchconditions for example include a Negishi type reaction of anintermediate compound of Formula (V) with a suitable palladium catalystsystem such as 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II), in a suitable solvent such as DMF, under suitablereaction conditions, such as at a convenient temperature, typicallyranging between 130° C. and 170° C., in particular 150° C., for a periodof time to ensure the completion of the reaction. Stirring and microwaveirradiation may enhance the rate of the reaction.

In Reaction Scheme 10, halo is defined as Cl, Br or I, R^(y) isC₁₋₄alkyl and all other variables are defined as in Formula (I).

Experimental Procedure 11

Intermediate compounds according to Formula (II-b) can be preparedfollowing art known procedures such as for example by an acidichydrolysis of an intermediate compound of Formula (II-f). The reactioncan be performed for example by heating a solution of nitrile of Formula(II-f) in a suitable solvent such as a solution of concentrated sulfuricacid. Alternatively an intermediate of Formula (II-b) can be prepared bya coupling reaction of a compound of Formula (II-a) with ammoniumchloride (NH₄Cl), according to conditions known to the skilled person.Such conditions for example include a suitable coupling agent such asHBTU, in presence of a suitable base such as DIPEA, in a suitablesolvent such as DMF, under suitable reaction conditions, such as at aconvenient temperature, typically room temperature (rt), for a period oftime to ensure the completion of the reaction. In Reaction Scheme 11,all variables are defined as in Formula (I).

Experimental Procedure 12

Intermediate compounds according to Formula (II-c) can be preparedfollowing art known procedures such as for example by a palladiumcatalyzed carbonylation reaction of an intermediate compound of Formula(V) using a carbon monoxide surrogate such as a phenylformate typederivative. Such conditions for example include the use of for example(2,4,6-trichlorophenyl)formate and a suitable palladium catalyst systemsuch as palladium(II) acetate, in the presence of a ligand such as4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), in thepresence of a suitable base such as Et₃N in a suitable solvent such astoluene, under suitable reaction conditions, such as at a convenienttemperature, typically ranging between 60° C. and 80° C., in particular70° C., for a period of time to ensure the completion of the reaction.Phenylformate type derivative can be synthesized according to literatureprocedures. In Reaction Scheme 12, halo is defined as Br or I and allother variables are defined as in Formula (I).

Experimental Procedure 13

Intermediate compounds according to Formula (V) can be prepared by aGoldberg coupling reaction of a compound of Formula (VII-a) with anappropriate aryl/heteroaryl halide of Formula (VIII) where X is halo, inparticular bromo or iodo, according to conditions known to the skilledperson. Such conditions include for example using a suitable copper(I)catalyst such as copper(I) iodide, in the presence of a ligand, such asN,N-dimethylethylenediamine, in the presence of a base, such asinorganic carbonates, for example sodium carbonate (Na₂CO₃) or potassiumcarbonate (K₂CO₃), in a suitable solvent, such as toluene or a mixtureof toluene and DMF, under suitable reaction conditions, such as at aconvenient temperature, typically ranging between 100° C. and 140° C.,in particular 110° C., for a period of time to ensure the completion ofthe reaction. A compound of Formula (VIII) can be obtained commerciallyor made according to procedures known in the art.

Alternatively intermediate compound according to Formula (V) can beprepared via a reaction of halogenation of an intermediate of Formula(VII-b) with a halogenating reagent such as iodine, in the presence ofammonium cerium(IV) nitrate and in an inert solvent such asacetonitrile, under suitable reaction conditions, such as at aconvenient temperature, typically 70° C., for a period of time to ensurethe completion of the reaction.

In Reaction Scheme 13, halo is defined as Br or I and all othervariables are defined as in Formula (I).

Experimental Procedure 14

Intermediate compounds according to Formula (VII-b) can be prepared by aGoldberg coupling reaction of a compound of Formula (IX-a) with anappropriate aryl/heteroaryl halide of Formula (VIII) where X is halo, inparticular bromo or iodo, according to conditions known to the skilledperson. Such conditions include for example using a suitable copper(I)catalyst such as copper(I) iodide, in the presence of a ligand, such asN,N-dimethylethylenediamine, in the presence of a base, such asinorganic carbonates, for example Na₂CO₃ or K₂CO₃, in a suitablesolvent, such as toluene or a mixture of toluene and DMF, under suitablereaction conditions, such as at a convenient temperature, typicallyranging between 100° C. and 140° C., in particular 110° C., for a periodof time to ensure the completion of the reaction. A compound of Formula(VIII) can be obtained commercially or made according to proceduresknown in the art.

Intermediate compound according to Formula (IX-a) can be prepared byremoval of the protecting group, for example a Boc group(tert-butoxycarbonyl), in an intermediate of Formula (X-a), for examplein the presence of acidic media, such as hydrochloric acid, in an inertsolvent such as 1,4-dioxane or acetonitrile or ethyl acetate (EtOAc),under suitable reaction conditions, such as at a convenient temperature,such as from 15 to 80° C., typically 80° C. or from 15-30° C. dependingon the solvent system, for a period of time to ensure the completion ofthe reaction followed by treatment with a base such as Na₂CO₃, K₂CO₃ orNaHCO₃, under suitable reaction conditions, such as at a convenienttemperature, typically ranging between 0° C. and 40° C., in particularfrom 15 to 30° C., for a period of time to ensure the completion of thereaction.

Intermediate compound according to Formula (X-a) wherein R^(x) isC₁₋₄alkyl and PG is a protecting group, for example Boc, can be preparedby a Mitsunobu type reaction between an intermediate compound of Formula(XI-a) and an appropriate alcohol of Formula (XII), in the presence of asuitable triarylphosphine, such as triphenylphosphine or a suitabletrialkylphosphine, and a suitable dialkyl azodicarboxylate reagent, suchas di-tert-butyl azodicarboxylate or diethyl azodicarboxylate, in asuitable inert solvent, such as THF, under suitable reaction conditions,such as at a convenient temperature, typically ranging 0° C. and rt,e.g. 20° C., for a period of time to ensure the completion of thereaction. Intermediate compounds of Formula (XII) and of Formula (IX-a)can be obtained commercially or synthesized according to literatureprocedures.

In Reaction Scheme 14, R^(x) is C₁₋₄alkyl, PG is a protecting group, forexample Boc, and all other variables are defined as in Formula (I).

Experimental Procedure 15

Intermediate compounds according to Formula (VII-a) wherein halo isbromo or iodo can be prepared by removal of the protecting group, forexample a Boc group, in an intermediate of Formula (X-b), for example inthe presence of acidic media, such as hydrochloric acid, in an inertsolvent such as 1,4-dioxane or acetonitrile or ethyl acetate (EtOAc),under suitable reaction conditions, such as at a convenient temperature,such as from 15 to 80° C., typically 80° C. or from 15-30° C. dependingon the solvent system, for a period of time to ensure the completion ofthe reaction followed by treatment with a base such as Na₂CO₃, K₂CO₃ orNaHCO₃, under suitable reaction conditions, such as at a convenienttemperature, typically ranging between 0° C. and 40° C., in particularfrom 15 to 30° C., for a period of time to ensure the completion of thereaction.

Intermediate compound of Formula (X-b) wherein halo is defined as Br orI, R^(x) is C₁₋₄alkyl and PG is a protecting group, for example Boc, canbe prepared by a Mitsunobu type reaction between an intermediatecompound of Formula (XI-b) and an appropriate alcohol of Formula (XII),in the presence of a suitable triarylphosphine, such astriphenylphosphine, or a suitable trialkylphosphine, and a suitabledialkyl azodicarboxylate reagent, such as di-tert-butyl azodicarboxylateor diethyl azodicarboxylate, in a suitable inert solvent, such as THF,under suitable reaction conditions, such as at a convenient temperature,typically ranging 0° C. and rt, e.g. 20° C., for a period of time toensure the completion of the reaction. An intermediate compound ofFormula (XII) can be obtained commercially or synthesized according toliterature procedures.

Intermediate compound of Formula (IX-b) wherein R^(x) is C₁₋₄alkyl, canbe prepared via a reaction of halogenation of intermediate of Formula(XI-a) with a halogenating reagent such as N-iodosuccinimide, in aninert solvent such as DCM, under suitable reaction conditions, such asat a convenient temperature, typically rt, for a period of time toensure the completion of the reaction. Intermediate compound of Formula(IX-b), wherein R^(x) is methyl and halo is bromo, can be obtainedcommercially and is a particularly preferred material for use in thesynthesis, including large scale, of a variety of final compounds ofFormula (I) according to the general procedures described herein. Anintermediate compound of Formula (XI-a) can be obtained commercially orsynthesized according to literature procedures.

In Reaction Scheme 15, halo is, in particular bromo or iodo, R^(x) isC₁₋₄alkyl, PG is a protecting group, such as for example Boc, and allother variables are defined as in Formula (I).

Experimental Procedure 16

Intermediate compounds according to Formula (II-d) can be prepared by aGoldberg coupling reaction of a compound of Formula (XIII) with anappropriate aryl/heteroaryl halide of Formula (VIII) where X is halo, inparticular bromo or iodo, according to conditions known to the skilledperson. Such conditions include for example using a suitable copper(I)catalyst such as copper(I) iodide, in the presence of a ligand, such asN,N-dimethylethylenediamine, in the presence of a base, such asinorganic carbonates, for example sodium carbonate (Na₂CO₃) or potassiumcarbonate (K₂CO₃), in a suitable solvent, such as toluene or a mixtureof toluene and DMF, under suitable reaction conditions, such as at aconvenient temperature, typically ranging between 100° C. and 140° C.,in particular 110° C., for a period of time to ensure the completion ofthe reaction. A compound of Formula (VIII) can be obtained commerciallyor made according to procedures known in the art.

Intermediate compounds according to Formula (XIII) can be preparedfollowing art known procedures such as for example a transition metalcatalyzed carbon monoxide insertion reaction of an intermediate compoundof Formula (VII-a) according to conditions known to the skilled person.Such conditions for example include the use of carbon monoxide and asuitable palladium catalyst system such as palladium(II) acetate, in thepresence of a ligand such as dppf, in the presence of a suitable basesuch as Et₃N in a suitable solvent such as a mixture of 1,4-dioxane andMeOH or EtOH, under suitable reaction conditions, such as at aconvenient temperature, typically ranging between 70° C. and 90° C., inparticular 80° C., for a period of time to ensure the completion of thereaction.

In Reaction Scheme 16, R^(y) is C₁₋₄alkyl and all other variables aredefined as in Formula (I).

Experimental Procedure 17

Intermediate compounds according to Formula (II-d) wherein R^(y) isC₁₋₄alkyl can be prepared by a reaction of compound of Formula (II-b)with N,N-dimethylformamide dimethyl acetal (DMFDMA) according toconditions known to the skilled person. In Reaction Scheme 17, allvariables are defined as in Formula (I).

Experimental Procedure 18

Intermediate compounds according to Formula (II-e) wherein R^(2a) isselected from the group consisting of R⁵ (except hydrogen) and Het² canbe prepared by acylation of a compound of Formula (XIV) with anappropriate acid chloride of Formula (VI) according to conditions knownto the skilled person. Such conditions for example include the use of asuitable base such as, for example Et₃N, a suitable solvent such as forexample DCM. Cooling the reaction mixture can enhance the reactionoutcome.

Intermediate compounds according to Formula (XIV) can be preparedfollowing art known procedures such as for example a reduction of anintermediate of Formula (II-f), for example by means of catalytichydrogenation using a suitable metal such as for example Raney nickeland a suitable solvent such as 7 M ammonia solution in MeOH.

A compound of Formula (VI) can be obtained commercially or madeaccording to procedures known in the art. In Reaction Scheme 18, R^(2a)is selected from the group consisting of R⁵ (except hydrogen) and Het²and all other variables are defined as in Formula (I).

In order to obtain the HCl salt forms of the compounds, severalprocedures known to those skilled in the art can be used. In a typicalprocedure, for example, the free base can be dissolved in DIPE or Et₂Oand subsequently, a 6N HCl solution in 2-propanol or a 1N HCl solutionin Et₂O can be added dropwise. The mixture typically is stirred for 10minutes after which the product can be filtered off. The HCl saltusually is dried in vacuo.

It will be appreciated by those skilled in the art that in the processesdescribed above the functional groups of intermediate compounds may needto be blocked by protecting groups. In case the functional groups ofintermediate compounds were blocked by protecting groups, they can bedeprotected after a reaction step.

Pharmacology

The compounds provided in this invention are negative allostericmodulators (NAMs) of metabotropic glutamate receptors, in particularthey are negative allosteric modulators of mGluR2. The compounds of thepresent invention do not appear to bind to the glutamate recognitionsite, the orthosteric ligand site, but instead to an allosteric sitewithin the seven transmembrane region of the receptor. In the presenceof glutamate, the compounds of this invention decrease the mGluR2response. The compounds provided in this invention are expected to havetheir effect at mGluR2 by virtue of their ability to decrease theresponse of such receptors to glutamate, attenuating the response of thereceptor.

As used herein, the term “treatment” is intended to refer to allprocesses, wherein there may be a slowing, interrupting, arresting orstopping of the progression of a disease or an alleviation of symptoms,but does not necessarily indicate a total elimination of all symptoms.

Hence, the present invention relates to a compound according to thegeneral Formula (I), or a stereoisomeric form thereof, or an N-oxidethereof, or a pharmaceutically acceptable salt or a solvate thereof, inparticular, a compound of Formula (I) or a stereoisomeric form thereof,or a pharmaceutically acceptable salt or a solvate thereof for use as amedicament.

The invention also relates to the use of a compound according to thegeneral Formula (I), or a stereoisomeric form thereof, or an N-oxidethereof, or a pharmaceutically acceptable salt or a solvate thereof, inparticular, a compound of Formula (I) or a stereoisomeric form thereof,or a pharmaceutically acceptable salt or a solvate thereof, or apharmaceutical composition according to the invention for themanufacture of a medicament.

The invention also relates to a compound according to the generalFormula (I), or a stereoisomeric form thereof, or an N-oxide thereof, ora pharmaceutically acceptable salt or a solvate thereof, in particular,a compound of Formula (I) or a stereoisomeric form thereof, or apharmaceutically acceptable salt or a solvate thereof, or apharmaceutical composition according to the invention for use in thetreatment or prevention of, in particular treatment of, a condition in amammal, including a human, the treatment or prevention of which isaffected or facilitated by the neuromodulatory effect of allostericmodulators of mGluR2, in particular negative allosteric modulatorsthereof.

The present invention also relates to the use of a compound according tothe general Formula (I), or a stereoisomeric form thereof, or an N-oxidethereof, or a pharmaceutically acceptable salt or a solvate thereof, inparticular, a compound of Formula (I) or a stereoisomeric form thereof,or a pharmaceutically acceptable salt or a solvate thereof, or apharmaceutical composition according to the invention for themanufacture of a medicament for the treatment or prevention of, inparticular treatment of, a condition in a mammal, including a human, thetreatment or prevention of which is affected or facilitated by theneuromodulatory effect of allosteric modulators of mGluR2, in particularnegative allosteric modulators thereof.

The present invention also relates to a compound according to thegeneral Formula (I), or a stereoisomeric form thereof, or an N-oxidethereof, or a pharmaceutically acceptable salt or a solvate thereof, inparticular, a compound of Formula (I) or a stereoisomeric form thereof,or a pharmaceutically acceptable salt or a solvate thereof, or apharmaceutical composition according to the invention for use in thetreatment, prevention, amelioration, control or reduction of the risk ofvarious neurological and psychiatric disorders associated with glutamatedysfunction in a mammal, including a human, the treatment or preventionof which is affected or facilitated by the neuromodulatory effect ofnegative allosteric modulators of mGluR2.

Also, the present invention relates to the use of a compound accordingto the general Formula (I), or a stereoisomeric form thereof, or anN-oxide thereof, or a pharmaceutically acceptable salt or a solvatethereof, in particular, a compound of Formula (I) or a stereoisomericform thereof, or a pharmaceutically acceptable salt or a solvatethereof, or a pharmaceutical composition according to the invention forthe manufacture of a medicament for treating, preventing, ameliorating,controlling or reducing the risk of various neurological and psychiatricdisorders associated with glutamate dysfunction in a mammal, including ahuman, the treatment or prevention of which is affected or facilitatedby the neuromodulatory effect of negative allosteric modulators ofmGluR2.

In particular, the neurological and psychiatric disorders associatedwith glutamate dysfunction, include one or more of the following centralnervous system conditions or diseases: mood disorders; delirium,dementia, amnestic and other cognitive disorders; disorders usuallyfirst diagnosed in infancy, childhood or adolescence; substance-relateddisorders; schizophrenia and other psychotic disorders; somatoformdisorders; and hypersomnic sleep disorder.

In particular, the central nervous system disorder is a psychoticdisorder selected from the group of schizophrenia (in particular inantipsychotic-stabilized patients), schizophreniform disorder,schizoaffective disorder, delusional disorder, brief psychotic disorder,and substance-induced psychotic disorder.

In particular, the central nervous system disorder is asubstance-related disorder selected from the group of alcoholdependence, alcohol abuse, amphetamine dependence, amphetamine abuse,caffeine dependence, caffeine abuse, cannabis dependence, cannabisabuse, cocaine dependence, cocaine abuse, hallucinogen dependence,hallucinogen abuse, nicotine dependence, nicotine abuse, opioiddependence, opioid abuse, phencyclidine dependence, and phencyclidineabuse.

In particular, the central nervous system disorder is a mood disorderselected from the group of major depressive disorder, depression,treatment resistant depression, dysthymic disorder, cyclothymicdisorder, and substance-induced mood disorder.

In particular, the central nervous system disorder is a disorder usuallyfirst diagnosed in infancy, childhood, or adolescence selected frommental retardation, learning disorder, motor skills disorder,communication disorder, attention-deficit and disruptive behaviourdisorders (such as Attention-Deficit/Hyperactivity Disorder (ADHD)). Anadditional disorder usually first diagnosed in infancy, childhood, oradolescence is autistic disorder.

In particular, the central nervous system disorder is a cognitivedisorder selected from the group of dementia, in particular, dementia ofthe Alzheimer's type, vascular dementia, dementia due to HIV disease,dementia due to head trauma, dementia due to Parkinson's disease,dementia due to Huntington's disease, dementia due to Pick's disease,dementia due to Creutzfeldt-Jakob disease, and substance-inducedpersisting dementia.

In particular, the central nervous system disorder is an amnesticdisorder, such as substance-induced persisting amnestic disorder.

As already mentioned hereinabove, the term “treatment” does notnecessarily indicate a total elimination of all symptoms, but may alsorefer to symptomatic treatment in any of the disorders mentioned above.In particular, symptoms that may be treated include but are not limitedto, memory impairment in particular in dementia or in major depressivedisorder, age-related cognitive decline, mild cognitive impairment, anddepressive symptoms.

Of the disorders mentioned above, the treatment of dementia, majordepressive disorder, depression, treatment resistant depression,attention-deficit/hyperactivity disorder and schizophrenia, inparticular in antipsychotic-stabilized patients, are of particularimportance.

The fourth edition of the Diagnostic & Statistical Manual of MentalDisorders (DSM-IV) of the American Psychiatric Association provides adiagnostic tool for the identification of the disorders describedherein. The person skilled in the art will recognize that alternativenomenclatures, nosologies, and classification systems for neurologicaland psychiatric disorders described herein exist, and that these evolvewith medical and scientific progresses.

A skilled person will be familiar with alternative nomenclatures,nosologies, and classification systems for the diseases or conditionsreferred to herein. For example, the “American Psychiatric Association:Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition.Arlington, Va., American Psychiatric Association, 2013” (DSM-5™)utilizes terms such as depressive disorders, in particular, majordepressive disorder, persistent depressive disorder (dysthymia),substance-medication-induced depressive disorder; neurocognitivedisorders (NCDs) (both major and mild), in particular, neurocognitivedisorders due to Alzheimer's disease, vascular NCD (such as vascular NCDpresent with multiple infarctions), NCD due to HIV infection, NCD due totraumatic brain injury (TBI), NCD due to Parkinson's disease, NCD due toHuntington's disease, frontotemporal NCD, NCD due to prion disease, andsubstance/medication-induced NCD; neurodevelopmental disorders, inparticular, intellectual disability, specific learning disorder,neurodevelopmental motor disorder, communication disorder, andattention-deficit/hyperactivity disorder (ADHD); substance-relateddisorders and addictive disorders, in particular, alcohol use disorder,amphetamine use disorder, cannabis use disorder, cocaine use disorder,other hallucinogen use disorder, tobacco use disorder, opiod usedisorder, and phencyclidine use disorder; schizophrenia spectrum andother psychotic disorders, in particular, schizophrenia,schizophreniform disorder, schizoaffective disorder, delusionaldisorder, brief psychotic disorder, substance/medication-inducedpsychotic disorder; somatic symptom disorders; hypersomnolence disorder;and cyclothymic disorder (which under DSM-5™ falls under the bipolar andrelated disorders category). Such terms may be used by the skilledperson as an alternative nomenclature for some of the diseases orconditions referred to herein. An additional neurodevelopmental disorderincludes autism spectrum disorder (ASD), which encompasses according tothe DSM-5™, disorders previously known by the terms early infantileautism, childhood autism, Kanner's autism, high-functioning autism,atypical autism, pervasive developmental disorder not otherwisespecified, childhood disintegrative disorder, and Asperger's disorder.In particular, the disorder is autism. Specifiers associated with ASDinclude those where the individual has a genetic disorder, such as inRett syndrome or Fragile X syndrome.

Therefore, the invention also relates to a compound according to thegeneral Formula (I), or a stereoisomeric form thereof, or an N-oxidethereof, or a pharmaceutically acceptable salt or a solvate thereof, inparticular, a compound of Formula (I) or a stereoisomeric form thereof,or a pharmaceutically acceptable salt or a solvate thereof, for use inthe treatment of any one of the diseases mentioned hereinbefore.

The invention also relates to a compound according to the generalFormula (I), or a stereoisomeric form thereof, or an N-oxide thereof, ora pharmaceutically acceptable salt or a solvate thereof, in particular,a compound of Formula (I) or a stereoisomeric form thereof, or apharmaceutically acceptable salt or a solvate thereof, for use intreating any one of the diseases mentioned hereinbefore.

The invention also relates to a compound according to the generalFormula (I), or a stereoisomeric form thereof, or an N-oxide thereof, ora pharmaceutically acceptable salt or a solvate thereof, in particular,a compound of Formula (I) or a stereoisomeric form thereof, or apharmaceutically acceptable salt or a solvate thereof, for the treatmentor prevention, in particular treatment, of any one of the diseasesmentioned hereinbefore.

The invention also relates to the use of a compound according to thegeneral Formula (I), or a stereoisomeric form thereof, or an N-oxidethereof, or a pharmaceutically acceptable salt or a solvate thereof, inparticular, a compound of Formula (I) or a stereoisomeric form thereof,or a pharmaceutically acceptable salt or a solvate thereof, for themanufacture of a medicament for the treatment or prevention of any oneof the disease conditions mentioned hereinbefore.

The compounds of the present invention can be administered to mammals,preferably humans, for the treatment or prevention of any one of thediseases mentioned hereinbefore.

In view of the utility of the compounds of Formula (I), there isprovided a method of treating warm-blooded animals, including humans,suffering from any one of the diseases mentioned hereinbefore, and amethod of preventing in warm-blooded animals, including humans, any oneof the diseases mentioned hereinbefore.

Said methods comprise the administration, i.e. the systemic or topicaladministration, preferably oral administration, of a therapeuticallyeffective amount of a compound of Formula (I), a stereoisomeric formthereof, or an N-oxide thereof, or a pharmaceutically acceptable salt orsolvate thereof, in particular, a compound of Formula (I) or astereoisomeric form thereof, or a pharmaceutically acceptable salt or asolvate thereof, to warm-blooded animals, including humans.

Therefore, the invention also relates to a method for the preventionand/or treatment of any one of the diseases mentioned hereinbeforecomprising administering a therapeutically effective amount of acompound according to the invention to a subject in need thereof.

One skilled in the art will recognize that a therapeutically effectiveamount of the NAMs of the present invention is the amount sufficient tomodulate the activity of the mGluR2 and that this amount varies interalia, depending on the type of disease, the concentration of thecompound in the therapeutic formulation, and the condition of thepatient. Generally, an amount of NAM to be administered as a therapeuticagent for treating diseases in which modulation of the mGluR2 isbeneficial, such as the disorders described herein, will be determinedon a case by case by an attending physician.

Generally, a suitable dose is one that results in a concentration of theNAM at the treatment site in the range of 0.5 nM to 200 μM, and moreusually 5 nM to 50 μM. To obtain these treatment concentrations, apatient in need of treatment likely will be administered an effectivetherapeutic daily amount of about 0.01 mg/kg to about 50 mg/kg bodyweight, preferably from about 0.01 mg/kg to about 25 mg/kg body weight,more preferably from about 0.01 mg/kg to about 10 mg/kg body weight,more preferably from about 0.01 mg/kg to about 2.5 mg/kg body weight,even more preferably from about 0.05 mg/kg to about 1 mg/kg body weight,more preferably from about 0.1 to about 0.5 mg/kg body weight. Theamount of a compound according to the present invention, also referredto here as the active ingredient, which is required to achieve atherapeutically effect will, of course vary on case-by-case basis, varywith the particular compound, the route of administration, the age andcondition of the recipient, and the particular disorder or disease beingtreated. A method of treatment may also include administering the activeingredient on a regimen of between one and four intakes per day. Inthese methods of treatment the compounds according to the invention arepreferably formulated prior to admission. As described herein below,suitable pharmaceutical formulations are prepared by known proceduresusing well known and readily available ingredients.

The compounds of the present invention may be utilized in combinationwith one or more other drugs in the treatment, prevention, control,amelioration, or reduction of risk of diseases or conditions for whichcompounds of Formula (I) or the other drugs may have utility, where thecombination of the drugs together are safer or more effective thaneither drug alone. Examples of such combinations include the compoundsof the invention in combination with antipsychotic(s), NMDA receptorantagonists (e.g. memantine), NR2B antagonists, acetylcholinesteraseinhibitors (e.g. donepezil, galantamine, physostigmine and rivastigmine)and/or antidepressant neurotransmitter reuptake inhibitors. Particularcombinations include the compounds of the invention in combination withantipsychotics, or the compounds of the invention in combination withmemantine and/or NR2B antagonists.

Pharmaceutical Compositions

The present invention also provides compositions for preventing ortreating diseases in which modulation of the mGluR2 receptor isbeneficial, such as the disorders described herein. While it is possiblefor the active ingredient to be administered alone, it is preferable topresent it as a pharmaceutical composition. Accordingly, the presentinvention also relates to a pharmaceutical composition comprising apharmaceutically acceptable carrier or diluent and, as activeingredient, a therapeutically effective amount of a compound accordingto the invention, in particular a compound according to Formula (I), anN-oxide, a pharmaceutically acceptable salt thereof, a solvate thereofor a stereochemically isomeric form thereof, more in particular, acompound according to Formula (I), a pharmaceutically acceptable saltthereof, a solvate thereof or a stereochemically isomeric form thereof.The carrier or diluent must be “acceptable” in the sense of beingcompatible with the other ingredients of the composition and notdeleterious to the recipients thereof.

The compounds according to the invention, in particular the compoundsaccording to Formula (I), the N-oxides thereof, the pharmaceuticallyacceptable salts thereof, the solvates and the stereochemically isomericforms thereof, more in particular the compounds according to Formula(I), the pharmaceutically acceptable salts thereof, the solvates and thestereochemically isomeric forms thereof, or any subgroup or combinationthereof may be formulated into various pharmaceutical forms foradministration purposes. As appropriate compositions there may be citedall compositions usually employed for systemically administering drugs.

The pharmaceutical compositions of this invention may be prepared by anymethods well known in the art of pharmacy, for example, using methodssuch as those described in Gennaro et al. Remington's PharmaceuticalSciences (18^(th) ed., Mack Publishing Company, 1990, see especiallyPart 8: Pharmaceutical preparations and their Manufacture). To preparethe pharmaceutical compositions of this invention, a therapeuticallyeffective amount of the particular compound, optionally in salt form, asthe active ingredient is combined in intimate admixture with apharmaceutically acceptable carrier or diluent, which carrier or diluentmay take a wide variety of forms depending on the form of preparationdesired for administration. These pharmaceutical compositions aredesirable in unitary dosage form suitable, in particular, for oral,topical, rectal or percutaneous administration, by parenteral injectionor by inhalation. For example, in preparing the compositions in oraldosage form, any of the usual pharmaceutical media may be employed suchas, for example, water, glycols, oils, alcohols and the like in the caseof oral liquid preparations such as, for example, suspensions, syrups,elixirs, emulsions and solutions; or solid carriers such as, forexample, starches, sugars, kaolin, diluents, lubricants, binders,disintegrating agents and the like in the case of powders, pills,capsules and tablets. Because of the ease in administration, oraladministration is preferred, and tablets and capsules represent the mostadvantageous oral dosage unit forms in which case solid pharmaceuticalcarriers are obviously employed. For parenteral compositions, thecarrier will usually comprise sterile water, at least in large part,though other ingredients, for example, surfactants, to aid solubility,may be included. Injectable solutions, for example, may be prepared inwhich the carrier comprises saline solution, glucose solution or amixture of saline and glucose solution. Injectable suspensions may alsobe prepared in which case appropriate liquid carriers, suspending agentsand the like may be employed. Also included are solid form preparationsthat are intended to be converted, shortly before use, to liquid formpreparations. In the compositions suitable for percutaneousadministration, the carrier optionally comprises a penetration enhancingagent and/or a suitable wetting agent, optionally combined with suitableadditives of any nature in minor proportions, which additives do notintroduce a significant deleterious effect on the skin. Said additivesmay facilitate the administration to the skin and/or may be helpful forpreparing the desired compositions. These compositions may beadministered in various ways, e.g., as a transdermal patch, as aspot-on, as an ointment.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in unit dosage form for ease ofadministration and uniformity of dosage. Unit dosage form as used hereinrefers to physically discrete units suitable as unitary dosages, eachunit containing a predetermined quantity of active ingredient calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. Examples of such unit dosage forms aretablets (including scored or coated tablets), capsules, pills, powderpackets, wafers, suppositories, injectable solutions or suspensions andthe like, teaspoonfuls, tablespoonfuls, and segregated multiplesthereof.

Since the compounds according to the invention are orally administrablecompounds, pharmaceutical compositions comprising aid compounds for oraladministration are especially advantageous.

In order to enhance the solubility and/or the stability of the compoundsof Formula (I) in pharmaceutical compositions, it can be advantageous toemploy α-, β- or γ-cyclodextrins or their derivatives, in particularhydroxyalkyl substituted cyclodextrins, e.g.2-hydroxypropyl-β-cyclodextrin or sulfobutyl-β-cyclodextrin. Alsoco-solvents such as alcohols may improve the solubility and/or thestability of the compounds according to the invention in pharmaceuticalcompositions.

The exact dosage and frequency of administration depends on theparticular compound of formula (I) used, the particular condition beingtreated, the severity of the condition being treated, the age, weight,sex, extent of disorder and general physical condition of the particularpatient as well as other medication the individual may be taking, as iswell known to those skilled in the art. Furthermore, it is evident thatsaid effective daily amount may be lowered or increased depending on theresponse of the treated subject and/or depending on the evaluation ofthe physician prescribing the compounds of the instant invention.

Depending on the mode of administration, the pharmaceutical compositionwill comprise from 0.05 to 99% by weight, preferably from 0.1 to 70% byweight, more preferably from 0.1 to 50% by weight of the activeingredient, and, from 1 to 99.95% by weight, preferably from 30 to 99.9%by weight, more preferably from 50 to 99.9% by weight of apharmaceutically acceptable carrier, all percentages being based on thetotal weight of the composition.

The amount of a compound of Formula (I) that can be combined with acarrier material to produce a single dosage form will vary dependingupon the disease treated, the mammalian species, and the particular modeof administration. However, as a general guide, suitable unit doses forthe compounds of the present invention can, for example, preferablycontain between 0.1 mg to about 1000 mg of the active compound. Apreferred unit dose is between 1 mg to about 500 mg. A more preferredunit dose is between 1 mg to about 300 mg. Even more preferred unit doseis between 1 mg to about 100 mg. Such unit doses can be administeredmore than once a day, for example, 2, 3, 4, 5 or 6 times a day, butpreferably 1 or 2 times per day, so that the total dosage for a 70 kgadult is in the range of 0.001 to about 15 mg per kg weight of subjectper administration. A preferred dosage is 0.01 to about 1.5 mg per kgweight of subject per administration, and such therapy can extend for anumber of weeks or months, and in some cases, years. It will beunderstood, however, that the specific dose level for any particularpatient will depend on a variety of factors including the activity ofthe specific compound employed; the age, body weight, general health,sex and diet of the individual being treated; the time and route ofadministration; the rate of excretion; other drugs that have previouslybeen administered; and the severity of the particular disease undergoingtherapy, as is well understood by those of skill in the area.

A typical dosage can be one 1 mg to about 100 mg tablet or 1 mg to about300 mg taken once a day, or, multiple times per day, or one time-releasecapsule or tablet taken once a day and containing a proportionallyhigher content of active ingredient. The time-release effect can beobtained by capsule materials that dissolve at different pH values, bycapsules that release slowly by osmotic pressure, or by any other knownmeans of controlled release.

It can be necessary to use dosages outside these ranges in some cases aswill be apparent to those skilled in the art. Further, it is noted thatthe clinician or treating physician will know how and when to start,interrupt, adjust, or terminate therapy in conjunction with individualpatient response.

As already mentioned, the invention also relates to a pharmaceuticalcomposition comprising the compounds according to the invention and oneor more other drugs for use as a medicament or for use in the treatment,prevention, control, amelioration, or reduction of risk of diseases orconditions for which compounds of Formula (I) or the other drugs mayhave utility. The use of such a composition for the manufacture of amedicament as well as the use of such a composition for the manufactureof a medicament in the treatment, prevention, control, amelioration orreduction of risk of diseases or conditions for which compounds ofFormula (I) or the other drugs may have utility are also contemplated.The present invention also relates to a combination of a compoundaccording to the present invention and an additional drug selected fromthe group of antipsychotics; NMDA receptor antagonists (e.g. memantine);NR2B antagonists; acetylcholinesterase inhibitors (e.g. donepezil,galantamine, physostigmine and rivastigmine) and/or antidepressantneurotransmitter reuptake inhibitors. In particular, the presentinvention also relates to a combination of a compound according to thepresent invention and antipsychotic(s), or to a combination of acompound according to the present invention and memantine and/or an NR2Bantagonist. The present invention also relates to such a combination foruse as a medicine. The present invention also relates to a productcomprising (a) a compound according to the present invention, an N-oxidethereof, a pharmaceutically acceptable salt thereof or a solvatethereof, in particular, a pharmaceutically acceptable salt thereof or asolvate thereof, and (b) an additional component selected fromantipsychotics, NMDA receptor antagonists (e.g. memantine), NR2Bantagonists, acetylcholinesterase inhibitors and/or antidepressantneurotransmitter reuptake inhibitor(s), as a combined preparation forsimultaneous, separate or sequential use in the treatment or preventionof a condition in a mammal, including a human, the treatment orprevention of which is affected or facilitated by the neuromodulatoryeffect of mGluR2 allosteric modulators, in particular negative mGluR2allosteric modulators. More in particular the additional component (b)is selected from antipsychotic(s) or memantine and/or an NR2Bantagonist. The different drugs of such a combination or product may becombined in a single preparation together with pharmaceuticallyacceptable carriers or diluents, or they may each be present in aseparate preparation together with pharmaceutically acceptable carriersor diluents.

The following examples are intended to illustrate but not to limit thescope of the present invention.

Chemistry

Several methods for preparing the compounds of this invention areillustrated in the following Examples. Unless otherwise noted, allstarting materials were obtained from commercial suppliers and usedwithout further purification.

Hereinafter, “BEH” means bridged ethylsiloxane/silica hybrid; “Boc” or“BOC” means tert-Butyloxycarbonyl; “CI” means chemical ionisation; “CSH”means charged surface hybrid; “DAD” means diode-array detector; “THF”means tetrahydrofuran; “Et₃N” means triethylamine; “DIPE” meansdiisopropylether; “DMAP” means 4-(dimethylamino)pyridine, “DMF” meansN,N-dimethylformamide; “dppf” means1,1′-bis(diphenylphosphino)ferrocene, “Et₂O” means diethylether; “EtOAc”means ethyl acetate; “EDCI.HCl” meansN-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride, “DCM” meansdichloromethane; “DMSO” means dimethylsulfoxide; “DIPEA” meansdiisopropylethylamine, “L” means liter; “LRMS” means low-resolution massspectrometry/spectra; “HATU” means2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate; “HBTU” meansO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,“HPLC” means high performance liquid chromatography; “HRMS” meanshigh-resolution mass spectrometry/spectra; “mL” or “ml” meansmilliliter; “NH₄Ac” means ammonium acetate; “EtOH” means ethanol; “ES”means electrospray; “iPrOH” means isopropanol; “iPrNH₂” meansisopropylamine; “MeOH” means methanol; “MSD” means Mass SelectiveDetector; “PyBOP®” means(benzotriazol-1-yloxy)tripyrrolidino-phosphonium hexafluorophosphate isa registered trademark of Merck KGaA, “Xantphos” means4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, “Pd₂(dba)₃” meanstris(dibenzylideneacetone)dipalladium(0), “eq” means equivalent(s); “RP”means Reverse Phase; “rt” or “RT” mean room temperature; “M.p.” meansmelting point; “min” means minutes; “h” means hour(s); “s” meanssecond(s); “TOF” means time of flight; “QTOF” means Quadrupole-Time ofFlight; “sat.” means saturated; “SFC” means supercritical fluidchromatography; “sol.” means solution; “SQD” means Single QuadrupoleDetector; “UPLC” means Ultra Performance Liquid Chromatography.

Microwave assisted reactions were performed in a single-mode reactor:Initiator™ Sixty EXP microwave reactor (Biotage AB), or in a multimodereactor: MicroSYNTH Labstation (Milestone, Inc.).

Thin layer chromatography (TLC) was carried out on silica gel 60 F254plates (Merck) using reagent grade solvents. Open column chromatographywas performed on silica gel, particle size 60 Å, mesh=230-400 (Merck)using standard techniques. Automated flash column chromatography wasperformed using ready-to-connect cartridges from different vendors, onirregular silica gel, (normal phase disposable flash columns) ondifferent flash systems.

Nuclear Magnetic Resonance (NMR): For a number of compounds, ¹H NMRspectra were recorded either on a Bruker Avance III, on a Bruker DPX-400or on a Bruker AV-500 spectrometer with standard pulse sequences,operating at 400 MHz and 500 MHz, respectively. Chemical shifts (8) arereported in parts per million (ppm) downfield from tetramethylsilane(TMS), which was used as internal standard.

The stereochemical configuration for the compounds has been designated“R” or “S”; for some compounds, the stereochemical configuration hasbeen designated as “*R” or “*S” when the absolute stereochemistry isundetermined although the compound itself has been isolated as a singlestereoisomer and is enantiomerically pure.

Synthesis of Intermediate Compounds Intermediate 1 (I-1) Ethyl1H-pyrazole-5-carboxylate (I-1)

Sulfuric acid (10 mL, 187.6 mmol) was added to a solution of1-H-pyrazole-3-carboxylic acid (1.93 g, 17.22 mmol) in EtOH (20 mL). Themixture was stirred at 90° C. for 15 h. Then it was allowed to cool tort and the solvents were evaporated in vacuo. The residue was pouredinto water and the solution basified with K₂CO₃ and extracted withEtOAc. The organic layer was separated, dried (MgSO₄), filtered and thesolvent evaporated in vacuo to yield intermediate compound I-1 as awhite solid (2.28 g, 93% purity, 94%) which was used in the followingstep without further purification.

Intermediate 2 (I-2) Ethyl 4-iodo-1H-pyrazole-5-carboxylate (I-2)

Intermediate I-1 (100 g, 0.68 mol), N-iodosuccinimide (213.5 g, 0.95mol) were dissolved in DCM (2 L). The mixture was stirred at rt for 24h. The mixture was treated with a sat. sol. of Na₂S₂O₃ and a sat. sol.of Na₂CO₃ and extracted with DCM. The organic layer was separated, dried(MgSO₄), filtered and the solvent evaporated in vacuo to yieldintermediate compound I-2 as a white solid (160 g, 85%).

Intermediate 3 (I-3) tert-Butyl N-[(2R)-2-hydroxypropyl]carbamate (I-3)

Di-tert-butyl dicarbonate (58.1 g, 266.3 mmol) in DCM (50 mL) was addedto a stirred solution of (R)-(−)-1-amino-2-propanol in DCM (50 mL) at 0°C. under nitrogen. The mixture was stirred at rt for 2 h. The mixturewas diluted with cooled water and extracted with DCM. The organic layerwas separated, dried (Na₂SO₄), filtered and the solvents evaporated invacuo to yield intermediate compound I-3 as a colorless oil (47 g,quant.). The product was used in the next step without furtherpurification.

Intermediate 4 (I-4) tert-Butyl N-(2-hydroxy-3-methoxy-propyl)carbamate(I-4)

Intermediate I-4 was synthesized following a similar approach describedfor I-3. Starting from 1-amino-3-methoxy-2-propanol (2.3 g, 21.9 mmol),and introducing a purification step (flash column chromatography(silica; MeOH in DCM 0/100 to 5/95)), I-4 (3.1 g, 69%) was obtained.

Intermediate 5 (I-5) Ethyl2-[(1S)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl]-4-iodo-pyrazole-3-carboxylate(I-5)

Di-tert-butyl azodicarboxylate (4.67 g, 20.3 mmol) was added to astirred solution of intermediate I-2 (3 g, 11.28 mmol), intermediate I-3(4.44 g, 22.55 mmol) and triphenylphosphine (5.32 g, 20.3 mmol) in THF(56 mL) under nitrogen. The mixture was stirred at rt for 5 h. Thesolvent was evaporated in vacuo and the crude product was trituratedwith DIPE. The solid was filtered and the filtrate was evaporated invacuo. The crude product was purified by flash column chromatography(silica; EtOAc in Heptane 0/100 to 30/70). The desired fractions werecollected and the solvents evaporated in vacuo to give intermediatecompound I-5 as a colorless oil (4.9 g, 91% purity, 93%).

Intermediate 6 (I-6) Ethyl2-[(1S)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl]pyrazole-3-carboxylate(I-6)

Intermediate compound I-6 was synthesized following a similar approachdescribed for intermediate I-5. Starting from intermediate I-1 (25.82 g,184.25 mmol) and intermediate I-3 (47.16 g, 239.5 mmol), intermediatecompound I-6 was obtained as a yellow oil (123 g, quant) which was usedin the following step without further purification.

Intermediate 7 (I-7) Ethyl2-[(1S)-2-amino-1-methyl-ethyl]-4-iodo-pyrazole-3-carboxylate.Hydrochloride Salt (I-7)

A 4M solution of HCl in 1,4-dioxane (10 mL, 40 mmol) was added to asolution of intermediate I-5 (4.2 g, 9.63 mmol) in acetonitrile (20 mL).The mixture was stirred at 80° C. for 2h. The solvent was evaporated invacuo to yield intermediate compound I-7 (3.5 g, 97%).

Intermediate 8 (I-8) Ethyl2-[(1S)-2-amino-1-methyl-ethyl]pyrazole-3-carboxylate. HydrochlorideSalt (I-8)

Intermediate compound I-8 was synthesized following a similar approachdescribed for intermediate I-7. Starting from intermediate I-6 (54.79 g,184.25 mmol) and a 4M solution of HCl in 1,4-dioxane (415 mL, 1.66 mol),intermediate compound I-8 was obtained as a white solid (32.5 g, 82%purity, 75%) which was used in the following step without furtherpurification.

Intermediate 9 (I-9)(7S)-3-Iodo-7-methyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (I-9)

Intermediate I-7 as HCl salt (180 g, 350.4 mmol) was dissolved in a sat.sol. of NaHCO₃ (2 L). The mixture was stirred at rt for 12 h. Themixture was diluted with water and extracted with DCM. The organiclayers were separated, dried (Na₂SO₄), filtered and the solventsevaporated in vacuo. Then the residue was washed with tert-butyl methylether to yield intermediate compound I-9 (92 g, 90%).

Intermediate 10 (I-10)(7S)-7-Methyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (I-10)

Intermediate compound I-10 was synthesized following a similar approachdescribed for intermediate I-9. Starting from intermediate I-8 (32.5 g,139.1 mmol), intermediate compound I-10 was obtained as a solid (14.8 g,70%).

Intermediate 11 (I-11) Ethyl2-[1-[(tert-butoxycarbonylamino)methyl]-2-methoxy-ethyl]pyrazole-3-carboxylate(I-11)

Di-tert-butyl azodicarboxylate (7.30 g, 31.68 mmol) was added to astirred solution of I-1 (1.78 g, 12.671 mmol), intermediate I-4 (3.12 g,15.21 mmol) and triphenylphosphine (8.31 g, 31.68 mmol) in THF (80 mL)under nitrogen at 0° C. The mixture was stirred at rt for 1 h. Thesolvent was evaporated and the residue was treated with DIPE, the solidwas filtered and the filtrate was evaporated in vacuo. The crude productwas purified by flash column chromatography (silica; EtOAc in heptane0/100 to 50/50). The desired fractions were collected and the solventsevaporated in vacuo to give intermediate compound I-11 (4 g, 96%).

Intermediate 12 (I-12) Ethyl2-[1-(aminomethyl)-2-methoxy-ethyl]pyrazole-3-carboxylate (I-12)

HCl (4 M in dioxane, 15.3 mL, 61.1 mmol) was added to a solution of I-11(4 g, 12.22 mmol) in MeCN (55.3 mL). The mixture was stirred at rt for 1h. The mixture was evaporated in vacuo to give intermediate compoundI-12 (2.77 g) which was used without any further purification.

Intermediate 13 (I-13)7-(Methoxymethyl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (I-13)

NaHCO₃ (sat. aqueous solution, 40 mL) was added to a solution ofintermediate I-12 (2.77 g, 12.189 mmol) in MeOH (14.205 mL). The mixturewas stirred at rt for 16 h. The mixture was diluted with water andextracted with DCM, EtOAc and THF/EtOAc 1:1. The organic layer wasseparated, dried (Na₂SO₄), filtered and the solvents evaporated in vacuoto give intermediate compound I-13 (1.92 g) which was used without anyfurther purification.

Intermediate 14 (I-14)4-Bromo-2-(methoxymethyl)-1-(trifluoromethyl)benzene (I-14)

NaH (60% dispersion in mineral oils, 368 mg, 9.20 mmol) was added to asolution of 5-bromo-2-(trifluoromethyl)-benzenemethanol (1.96 g, 7.666mmol) in THF (30.6 mL) at 0° C. and the mixture was stirred for 10 minat 0° C. Then methyl iodide (573 μL, 9.2 2799 mmol) was added and themixture was stirred at rt for 1 h. Then, additional methyl iodide (95μL, 1.5 mmol) was added and the mixture was stirred for 2 h. The mixturewas quenched with water and extracted with EtOAc. The organic layer wasseparated, washed with sat. sol. NaCl, dried (Na₂SO₄), filtered andconcentrated in vacuo to yield intermediate compound I-14 (2.06 g) whichwas used without any further purification.

Intermediate 15 (I-15)(7S)-7-Methyl-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazin-4-one(I-15)

A mixture of intermediate I-14 (5 g, 33.01 mmol), copper(I) iodide (3.78g, 19.85 mmol) and K₂CO₃ (9.14 g, 66.15 mmol) in toluene (150 mL) wasnitrogen flushed for a few min. Then 4-bromobenzotrifluoride (9.3 mL,66.1 mmol) and N,N-dimethylethylenediamine (2.1 mL, 19.8 mmol) wereadded. The mixture was stirred under nitrogen at rt for 10 min and thenstirred at 100° C. for 16 h. Then, DMF (20 mL) was added and the mixturewas stirred at 100° C. for 8 h. Then water, a conc. sol. of ammonia andDCM were added. The organic layer was separated, dried (Na₂SO₄),filtered and the solvents evaporated in vacuo. The crude product waspurified by flash column chromatography (silica; EtOAc in DCM 0/100 to50/50). The desired fractions were collected and the solvents evaporatedin vacuo to yield intermediate compound I-15 as a pale yellow oil (9.6g, 98%).

In a procedure analogous to that described for intermediate I-15, thefollowing intermediates were synthesized:

Starting Material Reagent Intermediate Product I-10

I-16 I-10

I-17 I-10

I-18 I-10

I-19 I-10

I-20(*) I-10

I-21 I-10

I-22(**) I-10

I-23 I-10

I-24 I-10

I-25 I-10

I-26 I-10

I-27 I-10

I-28 I-13

I-29 I-10

I-30 I-10

I-31 I-10

I-32 I-56

I-94 I-13

I-98 (*)Intermediate I-20 was also made according to the proceduredescribed below for I-34 using 2-chloro-5-(trifluoromethyl)pyridine asthe reagent. (**)Intermediate I-22 was also made according to theprocedure described below for I-34.

Intermediate 33 (I-33) 6-Chloro-2-methoxy-pyridin-3-amine (I-33)

Sodium methoxide (25 wt. % in MeOH, 3.7 mL, 64.8 mmol) was added to astirred solution of 3-amino-2,6-dichloropyridine (3 g, 18.4 mmol) in1,4-dioxane (30 mL). The mixture was stirred at 140° C. for 20 min undermicrowave irradiation. The mixture was treated with a sat. sol. NH₄Cland water and was stirred for 30 min. Then the mixture was extractedwith Et₂O, washed with brine, dried (Na₂SO₄), filtered and the solventsconcentrated in vacuo to yield intermediate compound I-33 (3.09 g,quant.) as a brown solid which was used in the following step withoutfurther purification.

Intermediate 34 (I-34) 6-Chloro-3-iodo-2-methoxy-pyridine (I-34)

To a suspension of copper(I) iodide (7.86 g, 41.3 mmol) and tert-butylnitrite (48 mL, 41.3 mmol) in MeCN (600 mL), intermediate I-33 in MeCN(600 mL) was added slowly at 0° C. for 5 min. The mixture was stirred at0° C. for 1 h. Then it was stirred at 65° C. for 1 h. The crude wasfiltered over celite. The mixture was diluted with water and extractedwith Et₂O. The organic phase was separated, dried (Na₂SO₄), filtered andthe solvents concentrated in vacuo to yield intermediate compound I-34(7.96 g, 71%) as a brown oil that was used in the next reaction stepwithout any further purification.

Intermediate 35 (I-35) 6-Chloro-2-methoxy-3-(trifluoromethyl)pyridine(I-35)

Copper(I) iodide (8.44 g, 44.3 mmol) was added to a stirred suspensionof intermediate I-34 (7.96 g, 29.53 mmol) and methylfluorosulphonyldifluoroacetate (8.6 mL, 67.9 mmol) in DMF (60 mL). Themixture was stirred at 100° C. for 16 h. The crude was filtered throughcelite. The mixture was diluted with Et₂O and extracted with a sat. sol.of NH₄C₁. The organic layer was separated, dried (Na₂SO₄), filtered andthe solvents concentrated in vacuo carefully (without heating) to yieldintermediate compound I-35 (8.92 g, 55% pure, 78%).

Intermediate 36 (I-36)(7S)-5-[6-Methoxy-5-(trifluoromethyl)-2-pyridyl]-7-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4-one(I-36)

Pd(PPh₃)₄ (4.39 g, 3.798 mmol) was added to a stirred suspension ofintermediate I-10 (5.74 g, 37.98 mmol), intermediate I-35 (14.88 g,37.98 mmol), Xantphos (4.40 g, 7.60 mmol), Cs₂CO₃ (24.75 g, 75.958 mmol)in 1,4-dioxane (140 mL) in a sealed tube and under nitrogen. The mixturewas stirred at 100° C. for 16 h. The mixture was filtered through a padof diatomaceous earth and washed with DCM. The organic layer wasevaporated in vacuo. The crude product was purified by flash columnchromatography (silica, EtOAc in DCM 0/100 to 50/50). The desiredfractions were collected, concentrated in vacuo. Then obtained productwas purified again by flash column chromatography (silica, EtOAc in DCM0/100 to 20/80). The desired fractions were collected, concentrated invacuo to yield intermediate compound I-36 (5.52 g, 44%) as a brown oilthat solidified upon standing at rt.

Intermediate 37 (I-37)(7S)-5-[3-(fluoromethyl)-4-(trifluoromethyl)phenyl]-7-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4-one(I-37)

Bis(2-methoxyethyl)amino-sulfur trifluoride (4.85 mL, 26.33 mmol) wasadded to a stirred solution of intermediate I-28 (1.71 g, 5.26 mmol) inDCM (30 mL) at 0° C. and under nitrogen. The mixture was allowed to warmup to rt and stirred at rt for 17 h. Then it was treated with a sat.sol. NaHCO₃ at 0° C. and extracted with EtOAc. The organic layer wasseparated, dried (Na₂SO₄), filtered and concentrated in vacuo. The crudeproduct was purified by flash column chromatography (silica; EtOAc inDCM 0/100 to 30/70). The desired fractions were collected andconcentrated in vacuo to yield intermediate compound I-37 (1.1 g, 64%)as colorless oil that solidified upon standing at rt.

Intermediate 38 (I-38)3-Iodo-7S-methyl-5-(4-trifluoromethyl-phenyl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (I-38)

Iodine (11.55 g, 45.5 mmol) was added to a solution of intermediate I-15(19.2 g, 65.0 mmol) and ammonium cerium(IV) nitrate (24.95 g, 45.5 mmol)in MeCN (350 mL). The mixture was stirred at 70° C. for 1 h. Then themixture was diluted with EtOAc and washed with a sat. sol. of Na₂S₂O₃and brine. The organic layer was separated, dried (Na₂SO₄), filtered andthe solvents evaporated in vacuo. The residue was precipitated with DIPEand then was purified by short column chromatography (silica, DCM) thenby flash column chromatography (silica; DCM in heptane 50/50 to 100/0).The desired fractions were collected and the solvents evaporated invacuo to yield intermediate compound I-38 as a solid (24.8 g, 90%).

In a procedure analogous to that described for intermediate I-38, thefollowing intermediates were synthesized:

Starting Material Intermediate obtained I-16

I-39 I-17

I-40 I-18

I-41 I-19

I-42 I-20

I-43 I-21

I-44 I-22

I-45 I-23

I-46 I-24

I-47 I-25

I-48 I-26

I-49 I-27

I-50 I-31

I-51 I-37

I-52 I-29

I-53 I-30

I-54 I-32

I-55 I-98

I-99

Intermediate 56 (I-56) Ethyl(7S)-7-methyl-4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazine-3-carboxylate(I-56)

Et₃N (12 mL, 86.62 mmol) was added to a mixture of intermediate I-9 (8g, 28.87 mmol), Pd(OAc)₂ (129 mg, 0.577 mmol) and dppf (640 mg, 1.155mmol) in EtOH (30 mL) and 1,4-dioxane (30 mL) under CO atmosphere (6atm) at 95° C. for 18 h. The mixture was diluted with sat. NaHCO₃ andEtOAc was added. The aqueous phase was extracted with EtOAc and DCM/MeOH9/1. The combined organics were dried (MgSO₄), filtered and evaporated.The crude product was purified by flash column chromatography (silica;EtOAc in DCM 5/100 to 70/30). The desired fractions were collected andconcentrated in vacuo to yield intermediate compound I-56 (5 g, 74%) asa beige solid.

Intermediate 56′(I-56′)

Intermediate 56′ was synthesized following a procedure analogous to thatdescribed for I-56, starting from I-9, and using Pd(dppf)Cl₂ as catalystand DMF as solvent. After the reaction took place, the reaction mixturewas filtered through diatomaceous earth, the solvents concentrated andthe crude product purified by flash column chromatography (silica; EtOAcin petroleum ether 1/10 to 1/0).

In a procedure analogous to that described for intermediate I-15, thefollowing intermediates were synthesized:

Starting Material Reagent Intermediate Product I-56

I-57 I-56

I-58  I-56′

I-58′ I-56

I-59  I-56′

I-I-59′ I-56

I-60 I-56

I-61 I-56

I-62 I-56

I-63 I-56

I-64  I-56′

I-64′

Intermediate 65 (I-65)(7S)-7-Methyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carbonitrile (I-65)

A mixture of intermediate I-35 (1.6 g, 3.80 mmol), zinc cyanide (579 mg,4.94 mmol) and PdCl₂(dppf) (139 mg, 0.19 mmol) in DMF (14.7 mL) wasstirred at 150° C. for 16 h. The crude product was filtered through apad of diatomaceous earth and the solvent was evaporated in vacuo. Thecrude product was purified by flash column chromatography (silica; DCM).The desired fractions were collected and evaporated in vacuo to giveintermediate compound I-65 (1.21 g, 99%).

Following a procedure analogous to that described for intermediate I-65,the following intermediate was also synthesized:

Starting Material Intermediate I-39

I-66 I-42

I-67 I-52

I-68

Intermediate 69 (I-69)(7S)-7-methyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide (I-69)

Procedure A): A mixture of intermediate I-65 (468 mg, 1.461 mmol) inconcentrated sulfuric acid (2.3 mL) was stirred at rt for 18 h. Themixture was poured onto ice and then it was carefully basified with anaq sol. NH₄OH. The mixture was extracted with EtOAc. The organic layerwas separated, dried (Na₂SO₄), filtered and the solvents concentrated invacuo to yield intermediate compound I-69 (488 mg, 99%) as a whitesolid.

Procedure B): HBTU (285 mg, 0.752 mmol) was added portionwise to astirred solution of intermediate I-74 (170 mg, 0.501 mmol), NH₄Cl (53mg, 1.002 mmol) and DIPEA (0.248 mL, 1.503 mmol) in DMF (5 mL). Themixture was stirred at rt for 3 days. The mixture was poured into sat.sol. NaHCO₃ and extracted with EtOAc. The organic layer was separated,dried (MgSO₄), filtered and evaporated in vacuo. The crude was purifiedby reverse phase from 75% H₂O (25 mM NH₄HCO₃)−25% MeCN—MeOH to 0% H₂O(25 mM NH₄HCO₃)−100% MeCN-MeOH. The desired fractions were collected andthe solvents concentrated in vacuo. The crude product was trituratedwith DIPE to yield intermediate compound I-69 (145 mg, 86%) as a whitesolid.

Intermediate 70 (I-70) Methyl(7S)-7-methyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxylate (I-70)

Procedure A): A mixture of intermediate I-38 (1.5 g, 3.56 mmol),Pd(OAc)₂ (16 mg, 0.071 mmol), dppf (78 mg, 0.142 mmol) and Et₃N (1.48mL, 10.68 mmol) in MeOH (15 mL) and 1,4-dioxane (15 mL) was stirredunder CO atmosphere (6 atm) at 95° C. for 18 h. The mixture was dilutedwith sat. sol. NaHCO₃ and EtOAc were added. The aqueous phase wasextracted once more. The combined organic layers were washed with water(×2), brine (×2), dried (MgSO₄), filtered and evaporated in vacuo. Thecrude product was purified by flash column chromatography (silica; EtOAcin Heptane 0/100 to 70/30). The desired fractions were collected andconcentrated in vacuo to yield intermediate compound I-70 (1.23 g, 95%)as a beige solid.

Procedure B): To a solution of intermediate I-69 (780 mg, 2.31 mmol) inMeOH (9.3 mL) was added N,N-dimethylformamide dimethyl acetal (0.92 mL,6.92 mmol) at rt. The mixture was stirred at 45° C. for 24 h. Themixture was diluted with sat. aq. NH₄Cl and extracted with DCM. Theorganic layer was dried (Na₂SO₄), filtered and concentrated in vacuo toyield intermediate I-70 (795 mg, 97%) as a white solid.

Following a procedure analogous to procedure A) described forintermediate I-70, the following intermediates were also synthesized:

Starting Material Intermediate Product I-54

I-71 I-51

I-72 I-53

I-73

Intermediate 74 (I-74)(7S)-7-methyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxylic acid (I-74)

Procedure A): NaOH (2 M in water, 0.743 mL, 1.486 mmol) was added to amixture of intermediate I-70 (500 mg, 1.415 mmol) in MeOH (5 mL). Themixture was stirred at 50° C. for 4 h. Then HCl (1 N) was added untilpH=4-5 at 0° C. The mixture was diluted with EtOAc and washed withwater. Then the organic layer was separated, dried (MgSO₄), filtered andthe solvent evaporated in vacuo to yield intermediate compound I-74 (500mg) as a beige solid which was used in the subsequent step withoutfurther purification.

Following a procedure analogous to procedure A) described forintermediate I-74, the following intermediates were also synthesized:

Starting Material Intermediate Product I-73

I-96

Procedure B): LiOH (2 mg, 0.078 mmol) was added to a stirred mixture ofintermediate I-70 (25 mg, 0.071 mmol) in 1,4-dioxane (1 mL) and water(0.1 mL) at rt. The mixture was stirred at rt for 24 h and the solventswere concentrated in vacuo to yield intermediate compound I-74 (23 mg,74%) which was used without further purification.

Procedure C): A stirred solution of intermediate I-65 (1.99 g, 6.213mmol) in HCl (3.9 mL, 37% in water) was stirred at 110° C. for 18 h.Then, HCl (3.9 mL, 37% in water) was added and the mixture was stirredat 110° C. for 16 h. The mixture was allowed to reach rt and then thesolvents were evaporated in vacuo. The residue was dissolved in waterand extracted with DCM. The organic layer was separated, dried (Na₂SO₄),filtered and the solvents evaporated in vacuo to give intermediatecompound I-74 (2 g, 95%) as a cream solid.

Intermediate 75 (I-75)(7S)-5-[3-(fluoromethyl)-4-(trifluoromethyl)phenyl]-7-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxylicacid I-75

Procedure D): Et₃N (0.174 mL, 1.257 mmol) was added to a mixture ofintermediate I-52 (170 mg, 0.375 mmol), Pd(OAc)₂ (2 mg, 0.008 mmol),dppf (9 mg, 0.016 mmol), 3-aminopyridine (35 mg, 0.375 mmol) in1,4-dioxane (30 mL). The mixture was stirred under CO atmosphere (6 atm)at 90° C. for 18 h. The mixture was filtered and concentrated in vacuo.The crude was purified by flash column chromatography (silica; DCM/MeOH9:1 in DCM 5/95 to 70/30). The desired fractions were collected andconcentrated in vacuo to yield intermediate compound I-75 (160 mg, 85%pure, 98%).

Following procedures A)-D) as indicated, analogous to those describedfor intermediates I-74 and I-75, the following compounds were alsosynthesized:

Starting Material Procedure Intermediate Product I-58 I-42 A) D)

I-76 I-59 I-40 A) D)

I-77 I-60 I-66 I-39 A) C) D)

I-78 I-71 A)

I-79 I-57 I-41 A) D)

I-80 I-62 A)

I-81 I-63 A)

I-82 I-64 I-44 A) D)

I-83 I-55 D)

I-84 I-47 D)

I-85

Intermediate 86 (I-86)(7S)-3-(aminomethyl)-7-methyl-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazin-4-one(I-86)

A solution of intermediate I-65 (440 mg, 1.374 mmol) in 7 M NH₃ in MeOH(26.4 mL) was hydrogenated in an H-Cube® reactor (Raney Ni shortcartridge, 1 mL/min, 80° C., full Hz, 2 cycles). The solvent wasconcentrated in vacuo to yield intermediate compound I-86 (460 mg, 98%)as a colorless oil.

Intermediate 87 (I-87) (2,4,6-Trichlorophenyl)(7S)-7-methyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxylate(I-87)

A mixture of intermediate I-38 (800 mg, 1.90 mmol), Pd(OAc)₂ (13 mg,0.057 mmol), Xantphos (66 mg, 0.114 mmol) and Et₃N (0.528 mL, 3.80 mmol)in 1,4-dioxane (4.8 mL) was degassed for 5 min and then it was stirredunder nitrogen at 70° C. for 5 min. Then a solution of2,4,6-trichlorophenyl formate (prepared as described in Org. Lett. 2014,5370-5373) (728 mg, 3.230 mmol) in degassed toluene (7.2 mL) was addedwith a syringe pump over 4 h. The crude product was filtered through afilter and the solvent was concentrated in vacuo. The crude product waspurified by flash column chromatography (silica; DCM). The desiredfractions were collected and evaporated in vacuo to give a residue whichwas purified by RP HPLC (Stationary phase: C₁₈ XBridge 30×100 mm 5 nm),Mobile phase: Gradient from 54% 0.1% NH₄CO₃H/NH₄OH pH 9 solution inWater, 46% MeCN to 64% 0.1% NH₄CO₃H/NH₄OH pH 9 solution in Water, 36%MeCN), to yield intermediate compound I-87 (390 mg, 80% pure, 31%).

Following a procedure analogous to that described for intermediate I-87,the following intermediates were also synthesized:

Starting Material Intermediate I-39

I-88

Intermediate 89 (I-89)(7S)—N-[[6-(2,5-Dimethylpyrrol-1-yl)-3-pyridyl]methyl]-7-methyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide(I-89)

HBTU (0.101 g, 0.266 mmol) was added portionwise to a stirred solutionof intermediate I-74 (60 mg, 0.177),6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-pyridinemethanamine (CAS:1531539-96-4, 43 mg, 0.212 mmol) and DIPEA (87.8 μL, 0.531 mmol) in DMF(3 mL). The mixture was stirred at rt for two days. The mixture wasdiluted with sat. NaHCO₃ aq. sol. and extracted with EtOAc. Then theorganic layer was separated, dried (MgSO₄), filtered and evaporated invacuo. The crude product was purified by flash column chromatography(silica; EtOAc in DCM 5/100 to 30/70). The desired fractions werecollected and the solvents concentrated in vacuo to yield intermediatecompound I-89 (75 mg, 80%) as a colorless oil.

Intermediate 90 (I-90)N-[[(7S)-7-methyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazin-3-yl]methyl]cyclobutanecarboxamide (I-90)

To a solution of intermediate I-86 (240 mg, 0.555 mmol), PyBOP® (289 mg,0.555 mmol) and Et₃N (116 μL, 0.832 mmol) in DCM (2.1 mL) was addedcyclobutanecarboxylic acid (56 mg, 0.555 mmol). The mixture was stirredat rt for 1 h. Then the mixture was diluted with water and extractedwith DCM. The organic layer was dried (Na₂SO₄), filtered andconcentrated in vacuo. The crude product was purified by flash columnchromatography (silica; 7N NH₃ in MeOH/DCM 0/100 to 3/97). The desiredfractions were collected and the solvents concentrated in vacuo. Theresidue was further purified by RP HPLC (Stationary phase: C18 XBridge30×100 mm 5 μm; mobile phase: gradient from 67% 0.1% NH₄CO₃H/NH₄OH pH 9solution in water, 33% MeCN to 50% 0.1% NH₄CO₃H/NH₄OH pH 9 solution inwater, 50% MeCN), to yield intermediate compound I-90 (145 mg, 64%).

Intermediate 91 (I-91)N-[[(7S)-7-methyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazin-3-yl]methyl]acetamide(I-91)

Acetyl chloride (52 μL, 0.74 mmol) was added to a stirred solution ofintermediate I-86 (0.24 g, 0.74 mmol) and Et₃N (103 μL, 0.74 mmol) inDCM (5 mL) at −78° C. under nitrogen. The mixture was stirred at −78° C.for 1 h and then quenched by the addition of sat. aq. Na₂CO₃. Themixture was allowed to reach rt and the organic layer was separated,dried (Na₂SO₄), filtered and the solvents concentrated in vacuo. Thecrude product was purified by flash column chromatography (silica; MeOHin DCM 0/100 to 8/92) to yield intermediate compound I-91 (230 mg, 76%pure, 64%).

A sample was purified by RP HPLC (Stationary phase: C18 Sunfire 19×100mm 5 μm, Mobile phase: Gradient from 80% 0.1% HCOOH solution in Water,20% MeCN to 0% 0.1% HCOOH solution in Water, 100% MeCN) and the residuewas dissolved in DCM and washed with aq. NaHCO₃. The organic layer wasdried (Na₂SO₄), filtered and the solvents concentrated in vacuo to yieldintermediate compound I-91 (20 mg) as a colorless oil.

Intermediate 92 (I-92)

Butyllithium (2.5M in hexanes, 13.3 mL, 33.21 mmol) was added dropwiseto a stirred solution of (5-fluoro-3-pyridinyl)-carbamic acid1,1-dimethylethyl ester (CAS: 342603-20-7, 2.82 g, 13.28 mmol) in THF(97 mL) at −78° C. (keeping Tint <−65° C.). The resulting mixture waswarmed to −30° C. and stirred at this temperature for 2 h. The solutionwas cooled to −78° C. and methyl iodide (3.3 mL, 53.15 mmol) was addeddropwise, (keeping Tint <−70° C.). The resulting solution was stirred at−78° C. for 1.5 h and then quenched by addition of water (5 mL). Themixture was diluted with EtOAc and water. The organic phase wasseparated, dried (Na₂SO₄), filtered and the solvents concentrated invacuo. The crude product was purified by flash column chromatography(silica; EtOAc in Heptane 0/100 to 30/70). The desired fractions werecollected and concentrated in vacuo to yield intermediate compound I-92(2.67 g, 89%) as a pale yellow oil.

Intermediate 93 (I-93)

Trifluoroacetic acid (4.54 mL, 59.00 mmol) was added to a stirredsolution of intermediate I-92 (2.67 g, 11.81 mmol) in DCM (42 mL). Themixture was stirred at rt for 1 h. The solvent was concentrated invacuo. The residue was dissolved in DCM and washed with a sat sol ofNa₂CO₃. The organic layer was separated, dried (Na₂SO₄), filtered andthe solvents concentrated in vacuo to yield intermediate compound I-93(1.07 g, 72%) as a pale brown solid. The aqueous phase was furtherextracted with DCM/EtOH (9/1). The organic layer was separated, dried(Na₂SO₄), filtered and the solvents concentrated in vacuo to yield asecond fraction of intermediate compound I-93 (460 mg, 83% pure, 25%) asa brown oil.

Following a sequence analogous to that described for compound I-93, thefollowing compounds were also synthesized:

Reagent Intermediate

I-94

I-95

Preparation of Final Compounds Example 1 (E-1)(7S)-7-methyl-4-oxo-N-(3-pyridyl)-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide(Co. No. 1)

DMAP (70 mg, 0.575 mmol) was added to intermediate I-74 (130 mg, 0.383mmol), 3-aminopyridine (36 mg, 0.383 mmol) in dry DCM (10 mL). Molecularsieves powder (1 g, 4 Å, activated) was added and the mixture wasstirred at rt for 1 h. EDCI.HCl (110 mg, 0.575 mmol) was addedportionwise and the mixture was stirred at rt for 24 h. The mixture wasfiltered through a pad of diatomaceous earth and the filtrate was washedtwice with 10% aq. NH₄Cl sol. The organic layers were combined, dried(MgSO₄), filtered and the solvents evaporated in vacuo. The crudeproduct was purified by flash column chromatography (silica; DCM/MeOH20:1 in DCM 5/95 to 70/30). The desired fractions were collected and thesolvents concentrated in vacuo. The solid was triturated with DIPE toyield final compound Co. No. 1 (141 mg, 87%) as a white solid. ¹H NMR(300 MHz, CDCl₃) δ ppm 1.79 (d, J=6.6 Hz, 3H) 4.06 (dd, J=12.9, 7.3 Hz,1H) 4.35 (dd, J=12.8, 4.3 Hz, 1H) 4.79-4.96 (m, 1H) 7.27-7.35 (m, 1H)7.57 (d, J=8.4 Hz, 2H) 7.82 (d, J=8.4 Hz, 2H) 8.23-8.41 (m, 2H) 8.37 (s,1H) 8.85 (br. s., 1H) 12.10 (br. s., 1H).

Following a procedure analogous to that described for E-1, the followingcompounds were also synthesized:

Intermediate Reagent Final Compound I-74

Co. No. 2 I-74

Co. No. 3 I-74

Co. No. 4 I-74

Co. No. 5 I-74

Co. No. 6 I-74

Co. No. 7 I-74

Co. No. 8 I-74

Co. No. 9 I-74

Co. No. 10 I-74

Co. No. 11 I-74

Co. No. 12 (free base) Co. No. 12a (HCl salt) I-74

Co. No. 13 (free base) Co. No. 13a (HCl salt) I-74

Co. No. 14 I-74

Co. No. 15 I-74

Co. No. 16 I-74

Co. No. 17 I-74

Co. No. 18 I-74

Co. No. 19 I-80

Co. No. 20 (**) I-80

Co. No. 21 (**) I-80

Co. No. 22 I-80

Co. No. 23 I-80

Co. No. 24 I-78

Co. No. 25 (**) I-78

No. 26 (**) I-78

Co. No. 27 I-78

Co. No. 28 I-78

Co. No. 29 I-78

Co. No. 30 I-85

Co. No. 31 I-82

Co. No. 32 I-82

Co. No. 33 I-82

Co. No. 34 I-77

Co. No. 35 (**) I-77

Co. No. 36 (‡)(**) I-77

Co. No. 37 I-77

Co. No. 38 I-77

Co. No. 39 I-77

Co. No. 40 I-83

Co. No. 41 (‡)(**) I-83

Co. No. 42 I-83

Co. No. 43 I-81

Co. No. 44 I-81

Co. No. 45 I-76

Co. No. 46 (**) I-76

Co. No. 47 (‡)(**) I-76

Co. No. 48 I-76

Co. No. 49 (•HCl) I-76

Co. No. 50 I-76

Co. No. 51 I-75

Co. No. 52 (**) I-75

Co. No. 53 I-75

Co. No. 54 (**) I-74

Co. No. 139 I-74

Co. No. 140 I-74

Co. No. 141 I-74

Co. No. 142 I-74

Co. No. 144 I-82

Co. No. 117 I-74

Co. No. 153 I-96

Co. No. 165 Co No. 165 was purified by Chiral SFC (Stationary phase:CHIRALPAK IC 5 μm 250 × 20 mm, Mobile phase: 60% CO2, 40% iPrOH) toyield Co. No. 158 and Co. No. 159

Co. No. 158

Co. No. 159 (‡) Compounds Co. No. 36, 41 and 47 were alternativelyprepared according to a method analogous to that described in E-8,starting from I-59′, I-64′and I-58′, respectively; (**) Compounds Co.No. 20, Co. No. 21, Co. No. 25, Co. No. 26, Co. No. 35, Co. No. 36, Co.No. 41, Co. No. 46, Co. No. 47, Co. No. 52, Co. No. 54 werealternatively prepared according to the method (different purificationreverse phase solvent systems) described below, which resulted in thedesired compound and the corresponding carboxylic acid species:

Example 1a (E-1a)

Et₃N (0.227 mL, 1.635 mmol) was added to a mixture of intermediate I-40(237 mg, 0.544 mmol), Pd(OAc)₂ (2 mg, 0.011 mmol), ddpf (12 mg, 0.022mmol), 3-aminopyridine (77 mg, 0.818 mmol) in 1,4-dioxane (30 mL)stirred at 90° C. for 18 h under CO atmosphere (6 atm). The mixture wasfiltered and the solvents concentrated in vacuo. The crude product waspurified by reverse phase from 75% H₂O (0.1% TFA)−25% MeCN to 38% H₂O(0.1% TFA)−62% MeCN. Product was neutralized, concentrated and extractedwith EtOAc to yield final compound Co. No. 36 (25 mg, 11%); intermediatecompound I-77 (149 mg, 74%) was used in the subsequent step withoutfurther purification.

Following a procedure analogous to that described for compound Co. No.36 and intermediate I-77 (E-1a), the following compounds andintermediates were also synthesized:

Intermediate Reagent Final Compound I-42

Co. No. 46 and

I-76 I-40

Co. No. 35 and

I-77 I-39

Co. No. 25 and

I-78 I-39

Co. No. 26 and

I-78 I-41

Co. No. 20 and

I-80 I-41

Co. No. 21 and

I-80 I-44

Co. No. 41 and

I-83 I-42

Co. No. 47 and

I-76 I-52

Co. No. 52 and

I-75 I-52

Co. No. 54 and

I-75 I-99

Co. No. 164 Co No. 164 was purified by Chiral SFC (Stationary phase:CHIRALPAK IC 5 μm 250 × 20 mm, Mobile phase: 60% CO2, 40% MeOH) to yieldCo. No. 156 and Co. No. 157.

Co. No. 156

Co. No. 157

Example 2 (E-2)(7S)—N-(6-fluoro-3-pyridyl)-7-methyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide(Co. No. 55)

DMAP (2 mg, 0.019 mmol) was added to a stirred mixture of intermediateI-87 (200 mg, 0.385 mmol), 5-amino-2-fluoropyridine (86 mg, 0.771 mmol)and Et₃N (161 μL, 1.156 mmol) in THF (6.7 mL) at rt under nitrogen. Themixture was stirred at 70° C. for 18 h. The solvent was concentrated invacuo. The crude product was purified by flash column chromatography(silica; 7N solution of ammonia in MeOH in DCM 0/100 to 3/97). Thedesired fractions were collected and the solvents evaporated in vacuo.The product was purified by RP HPLC (Stationary phase: C18 XBridge30×100 mm 5 μm), Mobile phase: Gradient from 54% 0.1% NH₄CO₃H/NH₄OH pH 9solution in Water, 46% MeCN to 64% 0.1% NH₄CO₃H/NH₄OH pH 9 solution inWater, 36% MeCN) to yield final compound Co. No. 55 (75 mg, 45%). ¹H NMR(400 MHz, CDCl₃) δ ppm 1.77 (d, J=6.7 Hz, 3H) 4.05 (dd, J=12.9, 7.4 Hz,1H) 4.33 (dd, J=12.8, 4.3 Hz, 1H) 4.85 (quind, J=6.7, 4.5 Hz, 1H) 6.89(dd, J=8.8, 3.2 Hz, 1H) 7.55 (d, J=8.3 Hz, 2H) 7.80 (d, J=8.6 Hz, 2H)8.28 (ddd, J=8.9, 7.1, 2.8 Hz, 1H) 8.34 (s, 1H) 8.45 (dd, J=2.3, 1.2 Hz,1H) 12.08 (br. s, 1H).

Following a procedure analogous to that described for E-2, the followingcompounds were also synthesized:

Intermediate Reagent Final compound I-87

I-88

Example 3 (E-3)(7S)-7-Methyl-4-oxo-N-phenyl-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide(Co. No. 57)

HBTU (251 mg, 0.663 mmol) was added portionwise to a stirred solution ofintermediate I-74 (150 mg, 0.442 mmol), aniline (48 μL, 0.53 mmol) andDIPEA (219 μL, 1.326 mmol) in DMF (3 mL). The mixture was stirred at rtfor 16 h. The mixture was diluted with sat. sol. NaHCO₃ and extractedwith EtOAc. Then the organic layer was separated, dried (MgSO₄),filtered and the solvents evaporated in vacuo. The crude product waspurified by reverse phase from 50% [25 mM NH₄HCO₃ pH=8]-50% [MeCN: MeOH1:1] to 0%[25 mM NH₄HCO₃ pH=8]−100% [MeCN: MeOH 1:1]. The desiredfractions were collected and the solvents concentrated in vacuo. Theproduct was triturated with DIPE to yield final compound Co. No. 57 (115mg, 62%) as a white solid. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.77 (d, J=6.6Hz, 3H) 4.02 (dd, J=12.9, 7.3 Hz, 1H) 4.32 (dd, J=12.9, 4.3 Hz, 1H)4.76-4.92 (m, 1H) 7.03-7.13 (m, 1H) 7.31 (t, J=7.9 Hz, 2H) 7.55 (d,J=8.2 Hz, 2H) 7.73 (d, J=7.6 Hz, 2H) 7.79 (d, J=8.4 Hz, 2H) 8.35 (s, 1H)11.86 (br. s., 1H).

Following a procedure analogous to that described for E-3, the followingcompounds were also synthesized:

Intermediate Reagent Final Compound I-74

I-74

I-74

I-74

I-74

I-74

I-74

I-74

I-74

I-74

I-74

I-74

I-74

I-74

I-74

I-74 NH₄Cl

I-76 NH₄Cl

I-77 NH₄Cl

I-78 NH₄Cl

I-80 NH₄Cl

I-80

I-81

I-82 NH₄Cl

I-82

I-83 NH₄Cl

I-81 NH₄Cl

I-96 NH₄Cl

Example 4 (E-4)(7S)-5-(5-Chloro-6-methoxy-2-pyridyl)-7-methyl-4-oxo-N-phenyl-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide(Co. No. 83)

A mixture of intermediate I-79 (100 mg, 0.297 mmol), aniline (30 μL,0.327 mmol), HATU (147 mg, 0.386 mmol) and DIPEA (119 μL, 0.683 mmol) inDMF (1.5 mL) was stirred at 80° C. for 16 h. The mixture was diluted inDCM and washed with sat. sol. NaHCO₃. The organic layer was separated,dried (Na₂SO₄), filtered and the solvents evaporated in vacuo. The crudeproduct was triturated with MeOH to yield final compound Co. No. 83 (75mg, 61%) as a pale yellow solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.73 (d,J=6.7 Hz, 3H) 4.03 (s, 3H) 4.34 (dd, J=13.6, 7.2 Hz, 1H) 4.56 (dd,J=13.6, 4.2 Hz, 1H) 4.79 (quind, J=6.7, 6.7, 6.7, 6.7, 4.3 Hz, 1H)7.05-7.15 (m, 1H) 7.29-7.40 (m, 2H) 7.61 (d, J=8.1 Hz, 1H) 7.74-7.77 (m,2H) 7.77 (d, J=8.3 Hz, 1H) 8.34 (s, 1H) 11.91 (br. s, 1H).

Following a procedure analogous to that described for E-4, the followingcompounds were also synthesized:

Intermediate Reagent Final Compound I-74

Example 5 (E-5)(7S)-5-[4-chloro-3-(difluoromethoxy)phenyl]-7-methyl-N-(2-methyl-4-pyridyl)-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide(Co. No. 84)

Et₃N (275 μL, 1.983 mmol) was added to a mixture of intermediate I-49(290 mg, 0.693 mmol), Pd(OAc)₂ (3 mg, 0.013 mmol), dppf (14 mg, 0.026mmol), 4-amino-2-methylpyridine (71 mg, 0.661 mmol) in 1,4-dioxane (30mL) was stirred under CO atmosphere (6 atm) at 90° C. for 18 h. Themixture was diluted with sat. sol. NaHCO₃ and extracted with EtOAc. Theorganic layer was separated, dried (MgSO₄), filtered and the solventsevaporated in vacuo. The crude product was purified by flash columnchromatography (silica; EtOAc in heptane 0/100 to 90/10). The desiredfractions were collected and the solvents concentrated in vacuo. Theproduct was triturated with pentane to yield final compound Co. No. 84(135 mg, 45%). ¹H NMR (300 MHz, CDCl₃) δ ppm 1.76 (d, J=6.5 Hz, 3H) 2.53(s, 3H) 3.99 (dd, J=12.9, 7.6 Hz, 1H) 4.26 (dd, J=12.9, 4.3 Hz, 1H)4.75-4.90 (m, 1H) 6.63 (t, J=72.7 Hz, 1H) 7.22-7.29 (m, 1H) 7.33 (s, 1H)7.47 (d, J=5.6 Hz, 1H) 7.50 (s, 1H) 7.61 (d, J=8.7 Hz, 1H) 8.32 (s, 1H)8.36 (d, J=5.6 Hz, 1H) 12.08 (br. s., 1H).

Following a procedure analogous to that described for E-5, the followingcompounds were also synthesized:

Intermediate Reagent Final Compound I-39

I-40

I-41

I-43

I-44

I-45

I-46

I-53

Then separated by chiral SFC (Stationary phase: CHIRALPAK IC 5 μm 250 x30 mm, Mobile phase: 60% CO₂, 40% EtOH(0.3% iPrNH₂)) - yielding 126 mgCo. No. 92 and 135 mg Co. No. 93

I-47

I-48

I-55

Example 6 (E-6)(7S)-5-(3,4-Dichlorophenyl)-N-(5-fluoro-2-pyridyl)-7-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide(Co. No. 98)

Pd₂(dba)₃ (24 mg, 0.026 mmol) and 2-bromo-5-fluoropyridine (78 mg, 0.442mmol) were added to a stirred mixture of compound Co. No. 76 (150 mg,0.442 mmol), Xantphos (26 mg, 0.044 mmol), K₃PO₄ (281 mg, 1.326 mmol) inTHF (6 mL) in a sealed tube and under nitrogen. The mixture was stirredat 90° C. for 4 h. The mixture was treated with sat. sol. NaHCO₃ andextracted with EtOAc. The organic layer was separated, dried (Na₂SO₄),filtered and the solvents concentrated in vacuo. The crude product waspurified by flash column chromatography (silica; EtOAc in Heptane 0/100to 50/50). The desired fractions were collected and the solventsconcentrated in vacuo to yield final compound Co. No. 98 (178 mg, 93%)as a cream solid after triturating with DIPE. ¹H NMR (400 MHz, CDCl₃) δppm 1.75 (d, J=6.7 Hz, 3H) 3.97 (dd, J=12.9, 7.4 Hz, 1H) 4.26 (dd,J=12.8, 4.3 Hz, 1H) 4.82 (quind, J=6.7, 4.4 Hz, 1H) 7.26 (dd, J=8.6, 2.5Hz, 1H) 7.43 (ddd, J=9.1, 7.8, 3.0 Hz, 1H) 7.51 (d, J=2.5 Hz, 1H) 7.55(d, J=8.6 Hz, 1H) 8.19 (d, J=3.0 Hz, 1H) 8.34 (s, 1H) 8.38 (dd, J=9.2,3.9 Hz, 1H) 12.39 (br. s, 1H).

Following a procedure analogous to that described for E-6, the followingcompounds were also synthesized:

Intermediate Reagent Final Compound I-69

I-69

I-69

I-69

I-69

I-69

I-69

I-69

Co. No. 74

Co. No. 74

Co. No. 74

Co. No. 74

Co. No. 75

Co. No. 75

Co. No. 75

Co. No. 77

Co. No. 77

Co. No. 80

Co. No. 76

Co. No. 76

Co. No. 80

I-69

I-69 (Procedure A)

I-69

Co. No. 166

Co. No. 166

Co. No. 82

Co. No. 163 was purified by Chiral SFC (Stationary phase: CHIRALCEL OD-H5 μm 250x20 mm, Mobile phase: 70% CO2, 30% iPrOH) to yield Co. No. 154and Co. No. 155. I-97

Example 7 (E-7)(7S)—N-(3-Methoxyphenyl)-5-[6-methoxy-5-(trifluoromethyl)-2-pyridyl]-7-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide(Co. No. 119)

Trimethylaluminium (2M in Heptane, 293 μL, 0.585 mmol) was added to astirred solution of m-anisidine (66 μL, 0.585 mmol) in THF (2.5 mL) at0° C. under nitrogen atmosphere. To this solution intermediate I-72 (150mg, 0.390 mmol) in THF (2 mL) was added at 0° C. The mixture was stirredat 150° C. for 5 min under microwave irradiation. The excess oftrimethylaluminium was quenched with HCl 1N and diluted with DCM. Theorganic layer was separated, dried (Na₂SO₄), filtered and the solventevaporated in vacuo. The crude product was purified by flash columnchromatography (silica, EtOAc in DCM 0/100 to 20/80). The desiredfractions were collected and the solvent evaporated in vacuo to yieldfinal compound Co. No. 119 (92 mg, 49%). as a white solid. ¹H NMR (400MHz, CDCl₃) δ ppm 1.74 (d, J=6.7 Hz, 3H) 3.84 (s, 3H) 4.06 (s, 3H) 4.40(dd, J=13.8, 7.3 Hz, 1H) 4.63 (dd, J=13.6, 4.2 Hz, 1H) 4.79 (quind,J=6.7, 4.3 Hz, 1H) 6.67 (ddd, J=7.6, 2.5, 1.6 Hz, 1H) 7.14-7.26 (m, 2H)7.58 (t, J=2.1 Hz, 1H) 7.78 (d, J=8.1 Hz, 1H) 8.00 (d, J=8.6 Hz, 1H)8.34 (s, 1H) 11.82 (br. s, 1H).

Following a procedure analogous to that described for E-7, the followingcompounds were also synthesized:

Intermediate Reagent Final Compound I-72

I-72

I-72

Example 8 (E-8)(7S)-7-Methyl-5-[3-methyl-4-(trifluoromethyl)phenyl]-4-oxo-N-(3-pyridyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide(Co. No. 36)

Isopropylmagnesium chloride lithium chloride complex solution (1.3 M inTHF, 12.6 mL, 16.33 mmol) was added to a stirred solution of3-aminopyridine (1.15 g, 12.25 mmol) in THF (49.5 mL) under nitrogen.The mixture was stirred at rt for 1 h. The resulting solution was addedto a stirred solution of intermediate I-59 (3 g, 8.16 mmol) in THF (49.5mL) and the mixture was stirred at 65° C. for 16 h. Moreisopropylmagnesium chloride lithium chloride complex solution (1.3 M inTHF, 6.3 mL, 8.16 mmol) was added and the mixture was stirred at 70° C.for 1 h. Water was added and the mixture was extracted with EtOAc. Theorganic layer was separated, dried (Na₂SO₄), filtered and the solventsconcentrated in vacuo. The crude product was purified by flash columnchromatography (silica; EtOAc in DCM 0/100 to 100/0). The desiredfractions were collected and the solvents concentrated in vacuo. Thecrude product was purified by flash column chromatography (silica; MeOHin DCM 0/100 to 10/90). The desired fractions were collected and thesolvents concentrated in vacuo. The residue was triturated with DIPE toyield final compound Co. No. 36 (2 g, 57%) as a white solid. ¹H NMR (500MHz, CDCl₃) δ ppm 1.76 (d, J=6.4 Hz, 3H) 2.58 (s, 3H) 4.01 (dd, J=13.0,7.2 Hz, 1H) 4.30 (dd, J=13.0, 4.3 Hz, 1H) 4.79-4.87 (m, 1H) 7.25 (dd,J=8.1, 4.6 Hz, 1H) 7.32 (d, J=8.4 Hz, 1H) 7.35 (s, 1H) 7.77 (d, J=8.4Hz, 1H) 8.24 (dt, J=8.4, 1.4 Hz, 1H) 8.32 (dd, J=4.6, 0.9 Hz, 1H) 8.34(s, 1H) 8.81 (d, J=2.3 Hz, 1H) 12.05 (br. s., 1H).

Following a procedure analogous to that described for E-8, the followingcompounds were also synthesized:

Intermediate Reagent Final Compound I-61

I-61

I-61 I-93

I-61

I-59 I-93

I-58

I-58 I-94

I-58 I-95

I-58

I-64

I-64 I-93

I-60 I-93

I-57 I-93

I-94

Example 9 (E-9)(7S)—N-(5-Fluoro-4-methyl-3-pyridyl)-7-methyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide(Co. No. 124)

Lithium bis(trimethylsilyl)amide (1M in THF, 0.653 mL, 0.653 mmol) wasadded to a stirred solution of intermediate I-93 (75 mg, 0.598 mmol) inTHF (5 mL) at 0° C. The mixture was stirred at 0° C. for 30 min, thenwas cooled to −10° C. and intermediate I-61 (200 mg, 0.544 mmol) in THF(3 mL) was added. The mixture was stirred at −10° C. for 1 h. Themixture was diluted with water and extracted with EtOAc. The organiclayer was separated, dried (Na₂SO₄), filtered and the solventsconcentrated in vacuo. The crude product was purified by flash columnchromatography (silica; EtOAc in DCM 0/100 to 20/80 and then 7N solutionof ammonia in MeOH in DCM 10/90). The desired fractions were collectedand the solvents concentrated in vacuo. The residue was triturated withDIPE to yield final compound Co. No. 124 (76 mg, 31%). as a pale salmonsolid. ¹H NMR (500 MHz, CDCl₃) δ ppm 1.78 (d, J=6.4 Hz, 3H) 2.25 (d,J=1.4 Hz, 3H) 4.05 (dd, J=12.9, 7.4 Hz, 1H) 4.34 (dd, J=12.9, 4.2 Hz,1H) 4.82-4.90 (m, 1H) 7.53 (d, J=8.4 Hz, 2H) 7.78 (d, J=8.4 Hz, 2H) 8.22(s, 1H) 8.36 (s, 1H) 8.94 (s, 1H) 11.56 (br. s, 1H).

Following a procedure analogous to that described for E-9, the followingcompounds were also synthesized:

Intermediate Reagent Final Compound I-61

I-61 I-95

Example 10 (E-10)(7S)-5-[3-chloro-4-(trifluoromethyl)phenyl]-N-(5-fluoro-4-methyl-3-pyridyl)-7-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide(Co. No. 133)

Intermediate I-93 (56 mg, 0.448 mmol) in THF (1 mL) was added to astirred solution of ethylmagnesium bromide (1M in THF, 0.448 mL, 0.448mmol) under nitrogen. The mixture was stirred at rt for 1 h. Theresulting solution was added to a stirred solution of intermediate I-58(150 mg, 0.373 mmol) in THF (0.84 mL) and the mixture was stirred at rtfor 18 h. Water was added and the mixture was extracted with EtOAc. Theorganic layer was separated, dried (Na₂SO₄), filtered and the solventsconcentrated in vacuo. The crude product was purified by flash columnchromatography (silica; EtOAc in DCM 0/100 to 20/80 and then 7N solutionof ammonia in MeOH in DCM 10/90). The desired fractions were collectedand the solvents concentrated in vacuo. The residue was triturated withDIPE to yield final compound Co. No. 133 (65 mg, 36%). as an off-whitesolid. ¹H NMR (500 MHz, CDCl₃) δ ppm 1.78 (d, J=6.4 Hz, 3H) 2.27 (d,J=1.4 Hz, 3H) 4.05 (dd, J=12.7, 7.5 Hz, 1H) 4.32 (dd, J=12.9, 4.2 Hz,1H) 4.86 (quind, J=6.9, 4.3 Hz, 1H) 7.43 (dd, J=8.4, 1.4 Hz, 1H) 7.59(d, J=2.0 Hz, 1H) 7.83 (d, J=8.4 Hz, 1H) 8.23 (br. s., 1H) 8.37 (s, 1H)8.95 (br. s., 1H) 11.44 (s, 1H).

Example 11 (E-11)

To a solution of intermediate I-69 or Co. No. 73 (30 mg, 0.0887 mmol) inDCM (0.568 mL) was added N,N-dimethylformamide dimethyl acetal (15.315μL, 0.115 mmol) at rt. Then 5 Å molecular sieves (50 mg) were added andthe mixture was stirred for at 70° C. for 40 min under microwaveirradiation. The mixture was filtered through a pad of diatomaceousearth and washed with DCM. The solvent was removed in vacuo and theresidue was purified by flash column chromatography (EtOAc in DCMgradient from 0:100 to 50:50). The desired fractions were collected andconcentrated in vacuo to yield final compound Co. No. 134 (19 mg,58.49%) as a white solid. ¹H NMR (500 MHz, CDCl₃) δ ppm 1.77 (d, J=6.6Hz, 3H) 4.04 (dd, J=13.0, 7.5 Hz, 1H) 4.32 (dd, J=13.0, 4.3 Hz, 1H) 4.85(quind, J=6.8, 4.3 Hz, 1H) 7.52 (d, J=8.4 Hz, 2H) 7.76 (d, J=8.4 Hz, 2H)8.34 (s, 1H) 9.34 (d, J=9.2 Hz, 1H) 12.35 (br. d, J=8.4 Hz, 1H).

Example 12 (E-12)(7S)-7-Methyl-N-(2-methylpyridine-4-carbonyl)-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide(Co. No. 135)

2-Methyl-4-pyridinecarbonyl chloride (80 mg, 0.514 mmol) was added to astirred mixture of intermediate I-69 (174 mg, 0.514 mmol) in pyridine(414 μL) under nitrogen. The mixture was stirred at 50° C. for 2 h. Thesolvent was concentrated in vacuo and the crude product was purified byflash column chromatography (silica, 7N solution of ammonia in MeOH inDCM 0:100 to 4:96) to yield a colorless oil which was further purifiedby RP HPLC (Stationary phase: C18 XBridge 30×100 mm 5 μm; mobile phase:gradient from 67% 0.1% NH₄CO₃H/NH₄OH pH 9 solution in water, 33% MeCN to50% 0.1% NH₄CO₃H/NH₄OH pH 9 solution in water, 50% MeCN) to yield finalcompound Co. No. 135 (11 mg, 5%). ¹H NMR (500 MHz, CDCl₃) δ ppm 1.77 (d,J=6.6 Hz, 3H) 2.55 (s, 3H) 4.09 (dd, J=13.0, 7.5 Hz, 1H) 4.36 (dd,J=13.0, 4.3 Hz, 1H) 4.86 (quind, J=6.9, 4.2 Hz, 1H) 7.56 (br. d, J=8.4Hz, 2H) 7.60 (dd, J=5.2, 1.2 Hz, 1H) 7.71 (br. s, 1H) 7.79 (br. d, J=8.4Hz, 2H) 8.36 (s, 1H) 8.60 (d, J=5.2 Hz, 1H) 13.12 (br. s, 1H).

Example 13 (E-13)(7S)—N-[(6-Amino-3-pyridyl)methyl]-7-methyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide(Co. No. 136)

A mixture of intermediate I-89 (75 mg, 0.144 mmol), hydroxylaminehydrochloride (50 mg, 0.72 mmol) and Et₃N (20 μL, 0.144 mmol) in EtOH (2mL) and water (1 mL) was stirred at reflux for 20 h. Hydroxylaminehydrochloride (50 mg, 0.72 mmol) and Et₃N (20 μL, 0.144 mmol) wereadded. The mixture was refluxed for an additional 12 h then cooled. Thecooled solution was quenched with HCl, washed with Et₂O, and the pH wasadjusted to 9-10 with 2 M NaOH. The resulting mixture was extractedseveral times with DCM. The combined organic phases were dried (MgSO₄)and the solvent was evaporated in vacuo. The crude product was purifiedby flash column chromatography (silica; DCM-MeOH 9/1 in DCM 5/100 to70/30). The desired fractions were collected and the solvents evaporatedin vacuo. The product was triturated with DIPE to yield final compound

Co. No. 136 (43 mg, 66%) as a white solid. ¹H NMR (300 MHz, CDCl₃) δ ppm1.65 (d, J=6.6 Hz, 3H) 3.89 (dd, J=12.8, 7.1 Hz, 1H) 4.20 (dd, J=12.8,4.3 Hz, 1H) 4.31 (br. s., 2H) 4.36 (d, J=5.8 Hz, 2H) 4.65-4.78 (m, 1H)6.36 (d, J=8.4 Hz, 1H) 7.37-7.45 (m, 3H) 7.68 (br. d, J=8.4 Hz, 2H) 7.94(d, J=1.5 Hz, 1H) 8.20 (s, 1H) 9.99 (br. t, J=5.1, 5.1 Hz, 1H).

Example 14 (E-14)(7S)—N-(cyclobutanecarbonyl)-7-methyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazine-3-carboxamide(Co. No. 137)

Dess-Martin periodinane (167 mg, 0.394 mmol) was added to a stirredsolution of intermediate I-90 (100 mg, 0.246 mmol) in fluorobenzene (2.5mL) and DMSO (100 μL) at rt. The resulting mixture was stirred in asealed tube at 85° C. for 1 h. The mixture was allowed to reach rt andthen it was partitioned between EtOAc and an aq. sol. of Na₂S₂O₃. Theorganic layer was dried (MgSO₄), filtered and the solvent concentratedin vacuo. The crude product was purified by flash column chromatography(silica; MeOH in DCM 10:90). The desired fractions were collected andthe solvents concentrated in vacuo to give a residue, which was furtherpurified by RP HPLC (Stationary phase: C18 XBridge 30×100 mm 5 μm;mobile phase: gradient from 54% 0.1% NH₄CO₃H/NH₄OH pH 9 solution inWater, 46% MeCN to 64% 0.1% NH₄CO₃H/NH₄OH pH 9 solution in water, 36%MeCN), to yield final compound Co. No. 137 (45 mg, 43%). ¹H NMR (500MHz, CDCl₃) δ ppm 1.74 (d, J=6.4 Hz, 3H) 1.81-1.90 (m, 1H) 1.91-2.02 (m,1H) 2.18-2.28 (m, 2H) 2.29-2.39 (m, 2H) 3.66 (quin, J=8.5 Hz, 1H) 4.02(dd, J=13.0, 7.2 Hz, 1H) 4.31 (dd, J=13.0, 4.3 Hz, 1H) 4.78-4.86 (m, 1H)7.52 (d, J=8.1 Hz, 2H) 7.76 (d, J=8.4 Hz, 2H) 8.28 (s, 1H) 12.18 (br.s., 1H).

Following a procedure analogous to that described for E-14, thefollowing compounds were also synthesized:

Intermediate Final compound I-91

Example 15 (E-15)(7S)—N-[5-(hydroxymethyl)pyridin-3-yl]-7-methyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide (Co. No.148)

Copper(I) iodide (45.6 mg, 0.240 mmol) was added to a stirred suspensionof intermediate I-69 (202.6 mg, 0.599 mmol), heteroaryl-halide[37669-64-0] (201.7 mg, 0.898 mmol) and K₃PO₄ (381.4 mg, 1.797 mmol) in1,4-dioxane (8.1 mL). The mixture was nitrogen flushed for a few minutesand then (+/−)-trans-1,2-cyclohexanediamine (28.8 μL, 0.240 mmol) andTEA (0.250 mL, 1.797 mmol) were added. The mixture was stirred undernitrogen in a sealed tube at 100° C. for 18 h. Then more TEA (0.250 mL,1.797 mmol) was added and stirred at 100° C. for 4 h. Then the mixturewas diluted with NH₄OH/brine and extracted with EtOAc. The organic layerwas separated and evaporated in vacuo. The crude product was purified byflash column chromatography (silica; EtOAc in DCM 0/100 to 100/0). Thedesired fractions were collected and the solvents concentrated in vacuo.The crude product was triturated with DIPE, filtered and dried to yieldfinal compound Co. No. 148 (122 mg, 46%) as a white solid.

Following a procedure analogous to that described for E-15, thefollowing compounds were also synthesized:

Intermediate Reagent Final compound I-69

I-69

I-69

Table 1 below lists additional compounds of Formula (I).

TABLE 1 The following compounds were prepared following the methodsexemplified in the Experimental Part (Ex. No.). Compounds exemplifiedand described in the experimental part are marked with an asterisk *.For some compounds the stereochemical configuration has been designatedas *R or *S when the absolute stereochemistry is undetermined althoughthe compound itself has been isolated as a single stereoisomer and isenantiomerically pure.

Co. No. R¹ R² >CR³R⁴ Salt Form  1

>CH(CH₃) (S)  2

>CH(CH₃) (S) 57

>CH(CH₃) (S)  3

>CH(CH₃) (S) 85

>CH(CH₃) (S) 86

>CH(CH₃) (S) 19

>CH(CH₃) (S)  4

>CH(CH₃) (S) 56

>CH(CH₃) (S)  5

>CH(CH₃) (S)  6

>CH(CH₃) (S) 87

>CH(CH₃) (S) 23

>CH(CH₃) (S) 120 

>CH(CH₃) (S)  7

>CH(CH₃) (S) 144 

>CH(CH₃) (S) 55

>CH(CH₃) (S)  8

>CH(CH₃) (S) 119 

>CH(CH₃) (S) 88

>CH(CH₃) (S) 121 

>CH(CH₃) (S) 89

>CH(CH₃) (S)  9

>CH(CH₃) (S) 83

>CH(CH₃) (S) 90

>CH(CH₃) (S) 58

>CH(CH₃) (S) 91

>CH(CH₃) (S) 10

>CH(CH₃) (S) 122 

>CH(CH₃) (S) 59

>CH(CH₃) (S) 60

>CH(CH₃) (S) 99

>CH(CH₃) (S) 134 

>CH(CH₃) (S) 61

>CH(CH₃) (S) 62

>CH(CH₃) (S) 63

>CH(CH₃) (S) 64

>CH(CH₃) (S) 65

>CH(CH₃) (S) 66

>CH(CH₃) (S) 67

>CH(CH₃) (S) 68

>CH(CH₃) (S) 69

—CH₃ >CH(CH₃) (S) 135 

>CH(CH₃) (S) 70

>CH(CH₃) (S) 136 

>CH(CH₃) (S) 20

>CH(CH₃) (S) 100 

>CH(CH₃) (S) 101 

>CH(CH₃) (S) 46

>CH(CH₃) (S) 94

>CH(CH₂OCH₃) (*S) 93

>CH(CH₂OCH₃) (*R) 71

>CH(CH₃) (S) 72

>CH(CH₃) (S) 35

>CH(CH₃) (S) 25

>CH(CH₃) (S) 11

>CH(CH₃) (S) 12  12a

>CH(CH₃) (S)   •HCl 92

>CH(CH₂OCH₃) 31

>CH(CH₃) (S) 102 

>CH(CH₃) (S) 103 

>CH(CH₃) (S) 104 

>CH(CH₃) (S) 137 

>CH(CH₃) (S) 95

>CH(CH₃) (S) 105 

>CH(CH₃) (S) 96

>CH(CH₃) (S) 13  13a

>CH(CH₃) (S)   •HCl 14

>CH(CH₃) (S) 138 

>CH(CH₃) (S) 84

>CH(CH₃) (S) 97

>CH(CH₃) (S) 139 

>CH(CH₃) (S) 53

>CH(CH₃) (S) 54

>CH(CH₃) (S) 140 

>CH(CH₃) (S) 141 

>CH(CH₃) (S) 17

>CH(CH₃) (S) 142 

>CH(CH₃) (S) 16

>CH(CH₃) (S) 52

>CH(CH₃) (S) 47

>CH(CH₃) (S) 15

>CH(CH₃) (S) 98

>CH(CH₃) (S) 26

>CH(CH₃) (S) 18

>CH(CH₃) (S) 37

>CH(CH₃) (S) 36

>CH(CH₃) (S) 106 

>CH(CH₃) (S) 112 

>CH(CH₃) (S) 109 

>CH(CH₃) (S) 124 

>CH(CH₃) (S) 133 

>CH(CH₃) (S) 116 

>CH(CH₃) (S) 118 

>CH(CH₃) (S) 107 

>CH(CH₃) (S) 108 

>CH(CH₃) (S) 126 

>CH(CH₃) (S) 132 

>CH(CH₃) (S) 127 

>CH(CH₃) (S) 111 

>CH(CH₃) (S) 110 

>CH(CH₃) (S) 28

>CH(CH₃) (S) 39

>CH(CH₃) (S) 40

>CH(CH₃) (S) 41

>CH(CH₃) (S) 21

>CH(CH₃) (S) 81

>CH(CH₃) (S) 29

>CH(CH₃) (S) 38

>CH(CH₃) (S) 32

>CH(CH₃) (S) 117 

>CH(CH₃) (S) 27

>CH(CH₃) (S) 78

>CH(CH₃) (S) 30

>CH(CH₃) (S) 33

>CH(CH₃) (S) 73

—H >CH(CH₃) (S) 75

—H >CH(CH₃) (S) 74

—H >CH(CH₃) (S) 76

—H >CH(CH₃) (S) 80

—H >CH(CH₃) (S) 77

—H >CH(CH₃) (S) 82

—H >CH(CH₃) (S) 128 

>CH(CH₃) (S) 113 

>CH(CH₃) (S) 34

>CH(CH₃) (S) 50

>CH(CH₃) (S) 115 

>CH(CH₃) (S) 24

>CH(CH₃) (S) 130 

>CH(CH₃) (S) 131 

>CH(CH₃) (S) 125 

>CH(CH₃) (S) 129 

>CH(CH₃) (S) 79

>CH(CH₃) (S) 143 

>CH(CH₃) (S) 22

>CH(CH₃) (S) 51

>CH(CH₃) (S) 123 

>CH(CH₃) (S) 43

>CH(CH₃) (S) 114 

>CH(CH₃) (S) 49

>CH(CH₃) (S) •HCl 44

>CH(CH₃) (S) 45

>CH(CH₃) (S) 48

>CH(CH₃) (S) 42

>CH(CH₃) (S) 145 

>CH(CH₃) (S) 146 

>CH(CH₃) (S) 147 

>CH(CH₃) (S) 148 

>CH(CH₃) (S) 149 

>CH(CH₃) (S) 150 

>CH(CH₃) (S) 151 

>CH(CH₃) (S) 152 

>CH(CH₃) (S) 153 

>CH₂ 154 

>CH(CH₂OCH₃) (*S) 155 

>CH(CH₂OCH₃) (*R) 156 

>CH(CH₂OCH₃) (*S) 157 

>CH(CH₂OCH₃) (*R) 158 

>CH(CH₂OCH₃) (*S) 159 

>CH(CH₂OCH₃) (*R) 160 

>CH(CH₃) (S) 161 

>CH(CH₃) (S) 162 

>CH(CH₃) (S) 163 

>CH(CH₂OCH₃) (RS) 164 

>CH(CH₂OCH₃) (RS) 165 

>CH(CH₂OCH₃) (RS) 166 

—H >CH(CH₃) (S) 167 

>CH(CH₃) (S)

The values of salt stoichiometry or acid content in the compounds asprovided herein, are those obtained experimentally and may vary whenusing different analytical methods. The content of hydrochloric acidreported herein was determined by ¹H NMR integration and/or elementalanalysis.

Analytical Part

Melting Points

Values are peak values, and are obtained with experimental uncertaintiesthat are commonly associated with this analytical method.

DSC823e (A): For a number of compounds, melting points (m.p.) weredetermined with a DSC823e (Mettler-Toledo) apparatus. Melting pointswere measured with a temperature gradient of 10° C./minute. Maximumtemperature was 300° C. Peak values were recorded.

Mettler Toledo MP50 (B): For a number of compounds, melting points weredetermined in open capillary tubes on a Mettler Toledo MP50. Meltingpoints were measured with a temperature gradient of 10° C./minute.Maximum temperature was 300° C. The melting point data was read from adigital display and checked from a video recording system.

LCMS

General Procedure

The High Performance Liquid Chromatography (HPLC) measurement wasperformed using a LC pump, a diode-array (DAD) or a UV detector and acolumn as specified in the respective methods. If necessary, additionaldetectors were included (see table of methods below).

Flow from the column was brought to the Mass Spectrometer (MS) which wasconfigured with an atmospheric pressure ion source. It is within theknowledge of the skilled person to set the tune parameters (e.g.scanning range, dwell time . . . ) in order to obtain ions allowing theidentification of the compound's nominal monoisotopic molecular weight(MW) and/or exact mass monoisotopic molecular weight. Data acquisitionwas performed with appropriate software.

Compounds are described by their experimental retention times (Rt) andions. If not specified differently in the table of data, the reportedmolecular ion corresponds to the [M+H]⁺ (protonated molecule). Formolecules with multiple isotopic patterns (Br, Cl), the reported valueis the one obtained for the lowest isotope mass. All results wereobtained with experimental uncertainties that are commonly associatedwith the method used.

TABLE 2 LC-MS Methods (Flow expressed in mL/min; column temperature (T)in ° C.; Run time in minutes). Method Instrument Column Mobile phaseGradient $\frac{Flow}{{Col}\mspace{14mu} T}$ Run time 1 Waters:Acquity ® Waters: CSH ™ C18 A: 95% CH₃COONH₄ From 95% A to 5% A$\frac{1}{50}$ 5 UPLC ® - (1.7 μm, 6.5 mM + in 4.6 min, DAD/SQD 2.1 × 50mm) 5% CH₃CN, held for B: CH₃CN 0.4 min 2 Waters: Acquity ® Waters:CSH ™ C18 A: 95% CH₃COONH₄ From 95% A to 5% A $\frac{1}{50}$ 5IClass-DAD/ (1.7 μm, 6.5 mM + in 4.6 min, Xevo G2-S 2.1 × 50 mm) 5%CH₃CN, held for QTOF B: CH₃CN 0.4 min 3 Waters: Acquity ® Waters: CSH ™C18 A: 95% CH₃COONH₄ From 95% A to 5% A $\frac{1}{50}$ 5 IClass UPLC ® -(1.7 μm, 6.5 mM + in 4.6 min, DAD/SQD 2.1 × 50 mm) 5% CH₃CN, held for B:CH₃CN 0.4 min 4 Agilent 1100- DAD-MSD YMC-pack ODS-AQ A: 0.1% HCOOH inFrom 95% A to 5% A $\frac{2.6}{35}$ 6.0 G1956A C18 (50 × 4.6 H₂O in 4.8min, mm, 3 μm) B: CH₃CN held for 1.0 min, to 95% A in 0.2 min. 5 Waters:Acquity Waters: BEH C18 (1.7 μm, A: 95% CH₃COONH₄ 84.2% A for 0.49 min,to $\frac{0.343}{40}$ 6.2 UPLC ® - 2.1 × 100 mm) 7 mM/5% 10.5% A inDAD/Quattro CH₃CN, 2.18 min, Micro ™ B: CH₃CN held for 1.94 min, back to84.2% A in 0.73 min, held for 0.73 min. 6 Agilent 1290 Infinity DADYMC-pack ODS-AQ A: 0.1% HCOOH in ISET 2V10 Emulated $\frac{2.6}{35}$ 6.0TOF-LC/MS C18 (50 × 4.6 H₂O Agilent G6224A mm, 3 μm) B: CH₃CN PumpG1312A V1.0 From 94.51% A to 5% A in 4.8 min, held for 1.0 min, to 95% Ain 0.2 min. 7 Waters: Acquity ® Waters: CSH ™ C18 A: 95% CH₃COONH₄ From95% A to 40% A $\frac{1}{50}$ 2 UPLC ® - (1.7 μm, 6.5 mM + 5% in 1.2min, DAD/SQD 2.1 × 50 mm) CH₃CN, B: to 5% A in CH₃CN 0.6 min, held for0.2 min 8 Agilent: HP1100-DAD, Agilent: Eclipse Plus A: 95% CH₃COONH₄95% A for 0.2 min, to $\frac{1}{60}$ 5 MSD G1956B C18 (3.5 μm, 6.5 mM +5% 0% A in 2.1 × 30 mm) CH₃CN, 2.8 min, B: CH₃CN held for 0.15 min, backto 95% A in 0.15 min, held for 1.7 min 9 Waters: Acquity ® Waters: CSH ™C18 A: 95% CH3COONH4 From 95% A to 5% A $\frac{1}{50}$ 5 IClass (1.7 μm,6.5 mM + 5% in 4.6 min, UPLC ® -DAD/ 2.1 × 50 mm) CH3CN, B: held forXevo G2-S CH3CN 0.4 min QTQF

TABLE 3 Analytical data - melting point (M.p.) and LCMS: [M + H]⁺ meansthe protonated mass of the free base of the compound, R_(t) meansretention time (in min), method refers to the method used for LCMS. Forsome compounds, exact mass was determined. Co. LCMS No. M.p. (° C.) [M +H]⁺ R_(t) Method  1 167.35 (A) 416.1333 (−0.1 mDa) 2.15 2  2 217.7 (B)493 3.60 4 57 n.d. 415 4.02 6  3 160.2 (B) 416 2.31 4 85 204.8 (B) 4312.40 6 86 121.8 (B) 444 2.52 6 19 181.5 (B) 431 2.25 6  4 189.0 (B) 4343.38 4 56 167.35 (A) 416.1333 (−0.1 mDa) 2.51 1  5 215.0 (B) 430 2.34 6 6 198.2 (B) 493 3.59 4 87 166.4 (B) 448 2.38 4 23 225.0 (B) 448 2.68 4120  167.35 (A) 416.1333 (−0.1 mDa) 3.08 8  7 185.3 (B) 433 3.90 6 144 197.8 (B) 446 3.31 4 55 n.d. 434 2.37 1  8 167.35 (A) 416.1333 (−0.1mDa) 2.31 2 119  194.51 (A) 476 2.95 2 88 244.9 (B) 431 2.27 4 121 212.39 (A) 476 3 2 89 171.4 (B) 396 2.20 6  9 246.7 (B) 416 3.41 6 83203.08 (A) 412 2.7 1 90 176.4 (B) 460 2.43 4 58 204.6 (B) 407 3.66 6 91224.9 (B) 455 2.29 4 10 171.6 (B) 430 2.53 4 122  192.95 (A) 476 2.91 259 159.8 (B) 421 3.89 6 60 161.4 (B) 393 3.45 6 99 223.3 (B) 431 3.16 6134  n.d. 367 1.93 1 61 186.7 (B) 407 3.77 4 62 231.4 (B) 423 3.36 4 63148.8 (B) 444 2.19 6 64 68.3 (B) 423 3.23 4 65 209.8 (B) 421 4.00 6 66n.d. 423 3.20 6 67 n.d. 429 3.81 6 68 n.d. 395 3.82 6 69 n.d. 353 3.15 6135  n.d. 458 1.97 1 70 128.8 (B) 437 3.33 4 136  104.2 (B) 445 2.15 620 199.2 (B) 434 3.69 4 100  225 (B) 417 3.50 4 101  214.9 (B) 444 2.414 46 223 (B) 450 3.84 4 94 n.d. 460 2.82 5 93 n.d. 460 2.82 5 71 208.2(B) 393 3.65 4 72 108.6 (B) 395 3.02 4 35 227.3 (B) 430 3.79 4 25 258.4(B) 416 3.69 4 11 164.7 (B) 446 2.62 4 12 n.d. 434 3.39 4 92 >300   4602.35 4 31 160.4 (B) 460 3.68 4 102  n.d. 446 3.72 4 103  248.3 (B) 4173.11 4 104  184.48 (A) 434.1237 (−0.3 mDa) 2.63 2 137  237.74 (A)421.1492 (+0.5 mDa) 2.41 2 95 n.d. 474 2.42 4 105  n.d. 446 3.98 4 96175.2 (B) 446 2.25 6 13 196.7 (B) 434 3.70 4  13a 146.4 (B) 434 3.70 414 249.5 (B) 430 2.44 6 138  212.65 (A) 381.1179 (+0.5 mDa) 1.91 2 84196.7 (B) 462 2.41 4 97 94.5 (B) 362 1.98 4 139  204.9 (B) 406 3.22 4 53145.5 (B) 448 2.89 4 54 141.3 (B) 462 2.46 4 140  246.7 (B) 422 3.69 4141  224.9 (B) 417 3.41 4 17 211.9 (B) 430 3.73 4 142  257.9 (B) 4052.18 4 16 200.8 (B) 446 2.46 4 52 197.4 (B) 448 2.40 4 47 120.57 and450.0959 (+1.5 mDa) 2.39 2 140.43 (A) (*) 15 136.3 (B) 430 2.62 4 98179.56 (A) 434.0589 (+0.2 mDa) 2.72 2 26 197.4 (B) 416 2.88 4 18 n.d.430 3.43 4 37 202.8 (B) 444 2.99 4 36 156.85 (A) 430.1508 (+1.7 mDa)2.32 2 106  n.d. 451.0906 (+0.9 mDa) 2.44 2 112  n.d. 431.1448 (+0.5mDa) 2.41 2 109  153.31 (A) 464.1101 (0.0 mDa) 2.5 2 124  194.50 (A) 4482.39 3 133  167.78 (A) 482 2.62 3 116  213.63 (A) 417 2.24 3 118  201.71(A) 444 2.39 3 107  189.26 A 478 2.5 3 108  212.88 (A) 468 2.76 3 126 229.17 (A) 478 2.5 3 132  224.82 (A) 460.1598 (+0.2 mDa) 2.35 2 127 185.94 (A) 494.1207 (0.0 mDa) 2.55 2 111  161.92 (A) 458.1803 (−0.1 mDa)2.53 2 110  221.63 (A) 448.1395 (−0.1 mDa) 2.78 2 28 233.4 (B) 430 2.874 39 144.6 (B) 448 3.90 4 40 194.8 (B) 460 3.45 4 41 180.0 (B) 382 2.564 21 179.0 (B) 434 2.94 4 81 186.35 (A) 466.1309 (+0.6 mDa) 2.53 2 29210.8 (B) 447 3.34 4 38 186.5 (B) 444 2.70 4 32 243.4 (B) 460 2.66 4117  259.0 (B) 464 3.72 4 27 174.0 (B) 434 3.80 4 78 183.36 (A) 452.1147(+0.1 mDa) 2.69 2 30 225.0 (B) 430 2.60 4 33 216.6 460 2.87 4 73 275 (B)339 2.92 4 75 n.d. 353.1225 (0.0 mDa) 1.87 2 74 n.d. 373.0685 (+0.6 mDa)1.94 2 76 n.d. 339 1.01 7 80 233.33 (A) 369 1.72 3 77 261.95 (A)415.1032 (+0.3 mDa) 1.79 2 [M + CH3COO]− (**) 82 n.d. 305 2.67 4 128 213.44 (A) 454 2.55 3 113  181.5 (B) 435 3.559 4 34 191.5 (B) 476 3.3174 50 168.1 (B) 468 3.91 4 115  193.3 (B) 447 3.519 4 24 204.0 (B) 4523.766 4 130  211.11 (A) 448.0744 (+0.1 mDa) 2.66 2 131  186.35 (A)466.1309 (+0.6 mDa) 2.53 2 125  156.83 (A) 462.1553 (0.0 mDa) 2.66 2129  189.99 (A) 414.1133 (0.0 mDa) 2.34 2 79 182.00 (A) 428.1291 (+0.2mDa) 2.56 2 143  201.6 (B) 474 2.59 4 22 246.7 (B) 448 2.92 4 51 214.9(B) 480 3.52 4 123  251.93 (A) 431 2.3 3 43 223.3 (B) 396 2.43 4 114 175.3 (B) 462 2.61 4 49 252.5 (B) 464 2.82 4 44 210.9 (B) 410 2.63 4 45165.9 (B) 414 3.79 4 48 216.6 (B) 464 3.08 4 42 186.5 (B) 400 3.54 4145  209.5 (A) 435.1194 (+0.2 mDa) 2.52 2 146  172.9 (A) 435.0545 (+0.6mDa) 2.59 2 147  212.57 (A) 446.1439 (−0.1 mDa) 1.75 2 148  150.83 (A)446.1439 (−0.1 mDa) 1.83 2 149  121.94 (A) 460.1600 (+0.4 mDa) 2.27 2150  169.28 (A) 446.1437 (−0.3 mDa) 1.91 2 151  152.64 (A) (*) 448.1402(+0.6 mDa) 2.35 2 152  145.36 (A) 466.0898 (+0.4 mDa) 2.43 2 153  229.9(B) 402 2.56 4 154  184.10 (A) 447.1393 (+0.1 mDa) 2.23 2 155  184.37(A) 447.1398 (+0.6 mDa) 2.23 2 156  105.42 (A) 480.1048 (−0.2 mDa) 2.412 157  n.d. 480.1054 (+0.4 mDa) 2.41 2 158  n.d. 446 1.2 7 159  n.d. 4462.15 1 160  178.1 (B) 424 2.53 4 161  233.4 (B) 397 3.54 4 162  250.1(B) 383 3.31 4 163  n.d. 447 3.48 4 164  n.d. 480.1063 (+1.3 mDa) 2.41 2165  n.d. 446.1436 (−0.4 mDa) 2.18 2 166  n.d. 319 2.93 4 167  205.04(A) (*) 495.0746 (−0.4 mDa)(***) 2.98 9 [M − H]⁻ n.d. = not determined(*) Multiple crystalline forms detected. MP related to the main/highestpeak (**) The compound was not directly ionizable. The type of adduct isspecified: [M + CH₃COO]⁻. (***)The reported molecular ion corresponds tothe [M − H]⁻(deprotonated molecule).Optical Rotations

Optical rotations were measured on a Perkin-Elmer 341 polarimeter with asodium lamp and reported as follows: [α]° (λ, c g/100 ml, solvent, T°C.). [α]_(λ) ^(T)=(100α)/(l×c): where l is the path length in dm and cis the concentration in g/100 ml for a sample at a temperature T (° C.)and a wavelength λ (in nm). If the wavelength of light used is 589 nm(the sodium D line), then the symbol D might be used instead. The signof the rotation (+ or −) should always be given. When using thisequation the concentration and solvent are always provided inparentheses after the rotation. The rotation is reported using degreesand no units of concentration are given (it is assumed to be g/100 ml).

TABLE 4 Optical Rotation data. Co. α_(D) Wavelength Concentration Temp.No. (°) (nm) w/v % Solvent (° C.) 128 +11.4 589 0.47 DMF 20 80 +16.2 5890.57 DMF 20 125 +8.6 589 0.53 DMF 20 130 +10.5 589 0.59 DMF 20 79 +8.4589 0.62 DMF 20 123 +9.4 589 1 DMF 20 55 +12.0 589 0.59 DMF 20 5 +8.4589 0.66 DMF 20 56 +9.2 589 0.45 DMF 20 122 −1.0 589 0.5 DMF 20 119 +3.6589 0.58 DMF 20 83 −1.1 589 0.49 DMF 20 104 +10.5 589 0.57 DMF 20 138+12.6 589 0.42 DMF 20 47 +8.9 589 0.83 DMF 20 98 +7.2 589 0.53 DMF 20 36+5.9 589 0.65 DMF 20 124 +7.9 589 0.58 DMF 20 133 +8.4 589 0.5 DMF 20116 +6.3 589 0.57 DMF 20 126 +9.1 589 0.66 DMF 20 132 +7.2 589 0.53 DMF20 127 +6.4 589 0.5 DMF 20 81 +9.4 589 0.55 DMF 20 129 +10.6 589 0.51DMF 20 118 +7.2 589 0.55 DMF 20 78 +10.5 589 0.51 DMF 20 77 +18.1 5890.57 DMF 20 145 +37.8 589 0.55 DMF 20 146 +35.2 589 0.55 DMF 20 147 +4.6589 0.50 DMF 20 148 +8.5 589 0.56 DMF 20 149 +9.8 589 1.10 DMF 20 150+9.7 589 0.52 DMF 20 151 +10.4 589 0.53 DMF 20 152 +9.1 589 0.58 DMF 20154 −25.4 589 0.49 DMF 20 155 +26.8 589 0.49 DMF 20 156 −32.7 589 0.51DMF 20 157 +27.6 589 0.49 DMF 20 158 −23.9 589 1.30 DMF 20 159 +25.5 5890.96 DMF 20 167 −22.5 589 0.50 DMF 20SFC-MSGeneral Procedure

The SFC measurement was performed using Analytical system from Bergerinstrument comprising a FCM-1200 dual pump fluid control module fordelivering carbon dioxide (CO₂) and modifier, a CTC Analytics automaticliquid sampler, a TCM-20000 thermal control module for column heatingfrom room temperature to 80° C. An Agilent 1100 UV photodiode arraydetector equipped with a high-pressure flow cell standing up to 400 barswas used. Flow from the column was split to a MS spectrometer. The MSdetector was configured with an atmospheric pressure ionization source.The following ionization parameters for the Waters ZQ massspectrophotometer are: corona: 9 μa, source temp: 140° C., cone: 30 V,probe temp 450° C., extractor 3 V, desolvatation gas 400 L/hr, cone gas70 L/hr. Nitrogen was used as the nebulizer gas. Data acquisition wasperformed with a Waters-Micromass MassLynx-Openlynx data system.

TABLE 5 Analytical SFC-MS Methods (Flow expressed in mL/min; columntemperature (T) in ° C.; Pressure in Mpa). Method Column Mobile PhaseFlow T Pressure 1 Chiralpak IC CO₂/EtOH (0.3% 3 35 100 150 mm × 4.6 mmIPrNH₂) 70/30 Daicel 2 Chiralcel OD-H CO₂/iPrOH(0.3% 3 35 100 150 mm ×4.6 mm IPrNH₂) 75/25 5 μm Daicel 3 Chiralpak IC CO₂/EtOH(0.3% 3 35 100150 mm × 4.6 mm IPrNH₂) 60/40 5 μm Daicel

TABLE 6 Analytical SFC data - R_(t) means retention time (in minutes),[M + H]⁺ means the protonated mass of the compound, method refers to themethod used for SFC/MS analysis of enantiomerically pure compounds. Themeasurement was compared against the mixture. Co. UV Area Isomer ElutionNo. R_(t) [M + H]⁺ % Order* Method 93 2.55 460 100 A 1 94 4.8 460 100 B1 155 2.96 447 100 A 2 154 4.07 447 100 B 2 157 2.76 480 100 A 3 1564.85 480 100 B 3 159 2.5 446 100 A 3 158 3.6 446 100 B 3 *A means thefirst isomer that elutes. B means the second isomer that elutes.

Pharmacological Examples

The compounds provided in the present invention are negative allostericmodulators of mGluR2. These compounds appear to inhibit glutamateresponses by binding to an allosteric site other than the glutamatebinding site. The response of mGluR2 to a concentration of glutamate isdecreased when compounds of Formula (I) are present. Compounds ofFormula (I) are expected to have their effect substantially at mGluR2 byvirtue of their ability to reduce the function of the receptor. Theeffects of negative allosteric modulators tested at mGluR2 using the[³⁵S]GTPγS binding assay method described below and which is suitablefor the identification of such compounds, and more particularly thecompounds according to Formula (I), are shown in Table 7.

A) In Vitro Pharmacology

1) [³⁵S]GTPγS Binding Assay

The [³⁵S]GTPγS binding assay is a functional membrane-based assay usedto study G-protein coupled receptor (GPCR) function wherebyincorporation of a non-hydrolysable form of GTP, [³⁵S]GTPγS (guanosine5′-triphosphate, labelled with gamma-emitting ³⁵S), is measured. TheG-protein a subunit catalyzes the exchange of guanosine 5′-diphosphate(GDP) by guanosine triphosphate (GTP) and on activation of the GPCR byan agonist, [³⁵S]GTPγS, becomes incorporated and cannot be cleaved tocontinue the exchange cycle (Harper (1998) Current Protocols inPharmacology 2.6.1-10, John Wiley & Sons, Inc.). The amount ofradioactive [³⁵S]GTPγS incorporation is a direct measure of the activityof the G-protein and hence the activity of the antagonist can bedetermined. mGlu2 receptors are shown to be preferentially coupled toGαi-protein, a preferential coupling for this method, and hence it iswidely used to study receptor activation of mGlu2 receptors both inrecombinant cell lines and in tissues. Here we describe the use of the[³⁵S]GTPγS binding assay using membranes from cells transfected with thehuman mGlu2 receptor and adapted from Schaffhauser et al. (MolecularPharmacology, 2003, 4:798-810) for the detection of the negativeallosteric modulation (NAM) properties of the compounds of thisinvention.

Membrane Preparation

CHO-cells were cultured to pre-confluence and stimulated with 5 mMbutyrate for 24 h. Cells were then collected by scraping in PBS and cellsuspension was centrifuged (10 min at 4000 RPM in benchtop centrifuge).Supernatant was discarded and pellet gently resuspended in 50 mMTris-HCl, pH 7.4 by mixing with an Ultra Turrax homogenizer. Thesuspension was centrifuged at 12,400 RPM (Sorvall F14S-6x250Y) for 10minutes and the supernatant discarded. The pellet was homogenized in 5mM Tris-HCl, pH 7.4 using an Ultra Turrax homogenizer and centrifugedagain (13,000 RPM, 20 min, 4° C.). The final pellet was resuspended in50 mM Tris-HCl, pH 7.4 and stored at −80° C. in appropriate aliquotsbefore use. Protein concentration was determined by the Bradford method(Bio-Rad, USA) with bovine serum albumin as standard.

[³⁵S]GTPγS Binding Assay

Measurement of mGluR2 negative allosteric modulatory activity of testcompounds was performed as follows. Test compounds and glutamate werediluted in assay buffer containing 10 mM HEPES acid, 10 mM HEPES salt,pH 7.4, 100 mM NaCl, 3 mM MgCl₂ and 10 μM GDP. Human mGlu2receptor-containing membranes were thawed on ice and diluted in assaybuffer supplemented with 18 μg/ml saponin. Membranes were pre-incubatedwith compound together with a predefined (˜EC₈₀) concentration ofglutamate (60 μM) for 30 min at 30° C. After addition of [³⁵S]GTPγS(f.c. 0.1 nM), assay mixtures were shaken briefly and further incubatedto allow [³⁵S]GTPγS incorporation on activation (30 minutes, 30° C.).Final assay mixtures contained 7 μg of membrane protein in 10 mM HEPESacid, 10 mM HEPES salt, pH 7.4, 100 mM NaCl, 3 mM MgCl₂, 10 μM GDP and10 μg/ml saponin. Total reaction volume was 2004 Reactions wereterminated by rapid filtration through Unifilter-96 GF/B plates (PerkinElmer, Massachusetts, USA) using a 96-well filtermate universalharvester. Filters were washed 6 times with ice-cold 10 mM NaH₂PO₄/10 mMNa₂HPO₄, pH 7.4. Filters were then air-dried, and 30 μl of liquidscintillation cocktail (Microscint-O) was added to each well.Membrane-bound radioactivity was counted in a Topcount.

Data Analysis

The concentration-response curves of representative compounds of thepresent invention were generated using the Lexis software interface(developed at J&J). Data were calculated as % of the control glutamateresponse, defined as the response that is generated upon addition of anEC₈₀-equivalent concentration of glutamate. Sigmoidconcentration-response curves plotting these percentages versus the logconcentration of the test compound were analyzed using non-linearregression analysis. The concentration producing half-maximal inhibitionwas calculated as the IC₅₀. The pIC₅₀ values were calculated as the −logIC₅₀, when the IC₅₀ is expressed in M. E_(max) is defined as therelative maximal effect (i.e. maximal % inhibition relative to thecontrol glutamate response).

TABLE 7 Pharmacological data for compounds according to the invention.GTPγS- GTPγS- hmGluR2 hmGluR2 Co. anGT anGT No. pIC₅₀ Emax 73 5.87 95 558.25 101 19 8.58 104 134  7.2 103  5 8.52 105 135  6.16 111 69 6.34 10366 6.73 103 57 8.77 102 68 6.58 102 65 6.75 107 67 6.7 104 136  5.81 104 7 8.33 103 59 7.45 103  9 7.95 103 99 7.34 100 63 6.93 99 60 7.36 10356 8.53 104  2 8.77 103  6 8.51 107 61 7.15 104 85 8.66 106 89 7.98 10786 8.64 105 91 7.73 103 90 7.8 106 88 8.07 106 87 8.46 112 58 7.74 11362 7.11 104 70 6.09 106 122  7.67 113 83 7.81 111 119  8.11 111 120  8.4107 121  8.01 109 64 6.77 107  3 8.68 116 144  8.32 114  1 8.72 111 107.7 113  4 8.52 117  8 8.36 123 14 8.61 109 95 8.26 112 13 8.65 110  13a8.96 106 96 8.53 113 105  8.21 108 137  7.39 107 104  8.09 108 103  6.99104 102  7.67 112 31 7.64 109 92 7.32 117 12 7.32 110 11 6.62 109 258.51 112 35 8.4 114 72 6.56 111 71 7.15 111 93 5.27 95 94 7.7 115 468.56 113 101  8.57 118 100  8.53 119 20 7.97 113 138  6.78 114 84 8.13112 97 6.83 114 139  7.59 109 53 8.61 114 54 8.28 118 140  8.03 111 141 8.08 113 17 7.39 107 142  6.67 110 16 7.86 115 52 8.59 118 47 8.97 10915 6.62 106 98 8.44 107 26 9.08 107 18 7.95 107 37 9.14 108 36 9.07 111106  8.94 111 112  8.95 106 109  8.91 109 124  8.65 107 133  9.04 105116  8.87 109 118  8.8 105 107  8.83 107 108  8.55 104 126  8.93 108132  7.91 105 127  8.39 108 111  8.84 109 110  8.3 107 28 9.06 107 399.03 112 40 8.67 111 41 8.21 106 21 8.72 108 81 7.71 106 29 8.75 107 388.94 108 32 8.46 111 117  8.43 105 27 9.09 108 78 7.87 106 30 8.96 11133 8.43 111 128  8.54 106 34 7.98 107 113  8.5 107 50 8.76 108 115  8.16108 24 8.49 107 131  8.53 110 125  8.63 110 130  9.07 110 129  8.21 11079 8.78 112 143  8.09 116 22 8.45 109 51 8.85 113 145  8.91 126 146 9.02 128 147  7.27 103 148  7.73 105 149  7.69 104 150  8.09 107 151 8.57 115 152  8.98 108 153  6.91 111 154  8.31 113 155  6.48 106 156 8.77 107 157  6.55 104 158  8.48 108 159  6.10 108 160  8.45 112 161 8.55 108 162  8.17 109 163  7.99 107 164  8.72 108 165  8.03 106 166  nodata 167  7.37 107B) In Vivo Pharmacology1) Reversal of LY-404039-Induced Decrease of Palpebral Opening inApomorphine-Challenged Rats.

Male Wiga Wistar rats (Crl:WI; Charles River Germany; 220±40 g) werehoused under standard laboratory conditions (21±2° C.; 50-65% relativehumidity; light-dark cycle set at 12 h; lights on at 6.00 h) and fastedovernight prior to the start of the experiments (tap water remainedavailable ad libitum). During the test period, they were housed inindividual cages. Palpebral opening was scored every 5 min over thefirst hour after injection of apomorphine (1.0 mg/kg, i.v.) in animalseither pretreated or not pretreated with LY-404039 (2.5 mg/kg, s.c.) at1 h prior to the apomorphine injection. The animals were also pretreatedwith test compound or solvent at a predefined interval beforeapomorphine challenge. The score system was: (5) exophthalmos, (4) wideopen, (3) open for three-quarters, (2) half open, (1) open forone-quarter, (0) closed. The scores for palpebral opening were cumulatedover the 60-min observation period. A cumulative palpebral openingscore >26 was selected for drug-induced reversal of theLY-404039-induced decrease of palpebral opening (occurrence in 3.2% ofcontrol animals pretreated with LY-404039 (n=154) versus in 99.5% ofcontrol rats not pretreated with LY-404039 (n=6335)).

Table 8 shows the palpebral opening score in control animals receivingapomorphine alone and in animals receiving apomorphine and LY-404039. Inanimals receiving apomorphine alone the median palpebral opening is 43whereas in animals receiving apomorphine and LY-404039, the medianpalpebral opening is 17. In animals treated with apomorphine alone, thepalpebral opening score is almost always (in 95.5% of the rats) greaterthan 34, whereas in animals treated with the combination(apomorphine+LY-404039) only 3.2% of the animals show a palpebralopening greater than 26.

TABLE 8 Palpebral opening score in control animals. ApomorphineApomorphine + alone LY-404039 Measurement (n = 6335) (n = 154) Palpebralopening score Median score: 43 17 Occurrence score > 26 (%): 99.5 3.2Occurrence score > 34 (%): 95.9 0.02) Reversal of the Effect of the mGluR2 PAM JNJ-42153605-InducedInhibition of Scopolamine-Induced HyperlocomotionApparatus

Motor activity was measured in microprocessor-based motor activityarenas (closed gray PVC cylinders with a height of 39 cm and a diameterof 31 cm). Each arena was placed on an infrared LED (8×8 LEDs) lit box(white PVC squared box; 40×40 cm²; height 12.5 cm. An infrared-sensitivetube camera and a white light source were mounted to the ceiling abovethe observation chamber to track the animal. The total distance traveled(cm) was recorded and analyzed using the Noldus Ethovision XT VideoTracking System (Version 7.0.418; Noldus, Wageningen, The Netherlands).The intensity of the light within the activity cages (measured in thecentre at the level of the floor) ranged between 4 and 8 LUX.

General Procedure

The rats were pretreated with test compound or vehicle at 60 min beforethe start of the activity recordings and placed into individual cages.The rats were challenged with JNJ-42153605(3-(cyclopropylmethyl)-7-(4-phenylpiperidin-1-yl)-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine;WO2010/130424; Cid et al. J. Med. Chem. 2012, 55, 8770-8789) (20 mg/kg,i.v.) 30 min before the start of the activity recording combined withscopolamine (0.16 mg/kg, i.v.) just before the start of the activitymeasurements. Immediately after the injection of scopolamine, the ratswere placed into the activity monitors and total distance traveled overthe first 30 min was measured.

Solvent-Pretreated Control Rats.

Frequency distributions obtained in a historical series ofsolvent-pretreated control rats are given in Table 9 below. Animalsreceiving the combination of JNJ-42153605 and scopolamine (n=433) almostalways traveled a distance of less than 1500 cm (<1500 cm) (only 2.5% ofthe control rats traveled a distance of more than 1500 cm (>1500 cm)).On the other hand, animals challenged with scopolamine alone (n=215)always traveled a total distance of more than 1500 cm (>1500 cm) andalmost always (in 95.8% of the rats) a distance of more than 4400 cm(>4400 cm). Rats that did not receive any challenge traveled almostalways a distance of more than 1500 cm (>1500 cm) (in 93.3% of the rats)and less than 4400 cm (<4400 cm) (in 98.9% of the rats). For reversal ofthe inhibitory effect of JNJ-42153605 on the scopolamine-inducedhyperlocomotion, the following all-or-none criteria were adopted: (1)reversal: total distance >1500 cm.

TABLE 9 Frequency distributions obtained in historical series ofsolvent- pretreated control rats. N_(tested) means number of animalstested. Median (cm) >1500 cm (%) >4400 cm (%) N_(tested) Combination 4802.5 0.0 433 No challenge 2618 93.3 1.1 638 Scopolamine 7246 100 95.8 2153) Induction of Mydriasis

The pupil diameter of Wiga rats was measured with a microscopicmicrometer (1 unit= 1/24 mm). Criteria for drug-induced effects: pupildiameter >25 units for mydriasis (in controls: 1.9%) 1 hpost-administration of the test compound (test 1) or 1, 2 or 3 hpost-administration of the test compound (test 2, wherein the maximumpupil diameter over the full 3 h period is reported).

Table 10 below provides the data obtained in the tests 1)-3) describedabove:

TABLE 10 Summary of data in tests 1)-3). In the table: SCOP JNJ-42153605means Reversal of the effect of JNJ 42153605 on scopolamine-inducedhyperlocomotion, APO LY-404039 means Reversal of LY-404039-induceddecrease of palpebral opening in apomorphine challenged rats, MYD meansInduction of mydriasis, ED₅₀ means median effective dose; PO means oralroute; SC means subcutaneous route. ED₅₀ (mg/kg) Co. SCOP JNJ- APO LY-MYD No. Route 42153605 404039 Test 1 Test 2 19 PO 0.79 5 PO 1.270.32 >10 7 PO >2.5 9 PO 0.32 >2.5 >10 85 PO 1.26 89 PO >2.5 86 PO 1.2688 >2.5 87 PO >2.5 3 PO 0.08 144 PO 1.01 1.99 1 PO 0.20 0.39 >40 4 PO1.01 8 PO 1.26 0.2 >10 14 PO 0.13 0.13 95 PO >2.5 13 PO 0.32 0.32 96 PO1.99 105 PO >2.5 104 PO >0.63 25 PO >2.5 >10 35 PO >2.5 >10 46 PO >2.51.99 101 PO 0.5 0.79 >10 100 PO 0.2 0.32 20 PO >2.5 >2.5 84 >2.5 140PO >2.5 141 PO >2.5 47 PO 0.5 32 98 PO >0.63 26 PO 0.32 5 18 PO >0.63 37PO >0.63 >0.63 36 PO 0.2 20 106 PO 0.32 112 PO 0.2 109 PO 0.32 32 124 PO0.2 >40 133 PO >0.63 116 PO 0.05 5 118 PO >0.63 >0.63 1.3 107PO >0.63 >0.63 108 PO >0.63 126 PO >0.63 >0.63 132 PO >0.63 127 PO >0.63111 PO 0.32 110 PO >0.63 28 PO >0.63 39 PO 0.32 5 40 PO >0.63 >0.63 41PO >0.63 0.32 21 PO 0.32 7.9 29 PO >0.63 38 PO 0.20 2 32 PO >0.63 117 PO0.51 >10 27 PO 0.32 >10 78 PO >0.63 30 PO 0.51 3.1 33 PO >0.63 147PO >0.63 151 PO >0.63 152 PO 0.08 154 PO 0.63 156 PO 0.20 158 PO >0.63160 PO >0.63 161 PO >0.63 162 PO 0.13 >10

Prophetic Composition Examples

“Active ingredient” as used throughout these examples relates to a finalcompound of Formula (I), the pharmaceutically acceptable salts thereof,the solvates and the stereochemically isomeric forms and the tautomersthereof.

Typical examples of recipes for the formulation of the invention are asfollows:

1. Tablets

Active ingredient 5 to 50 mg Di-calcium phosphate 20 mg Lactose 30 mgTalcum 10 mg Magnesium stearate 5 mg Potato starch ad 200 mg

In this Example, active ingredient can be replaced with the same amountof any of the compounds according to the present invention, inparticular by the same amount of any of the exemplified compounds.

2. Suspension

An aqueous suspension is prepared for oral administration so that each 1milliliter contains 1 to 5 mg of one of the active compounds, 50 mg ofsodium carboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg ofsorbitol and water ad 1 ml.

3. Injectable

A parenteral composition is prepared by stirring 1.5% by weight ofactive ingredient of the invention in 10% by volume propylene glycol inwater.

4. Ointment

Active ingredient 5 to 1000 mg Stearyl alcohol 3 g Lanoline 5 g Whitepetroleum 15 g Water ad 100 g

In this Example, active ingredient can be replaced with the same amountof any of the compounds according to the present invention, inparticular by the same amount of any of the exemplified compounds.

Reasonable variations are not to be regarded as a departure from thescope of the invention. It will be obvious that the thus describedinvention may be varied in many ways by those skilled in the art.

We claim:
 1. A method of treating a depressive disorder comprising administering a compound of Formula (I) to a patient in need thereof

or a stereoisomeric form thereof, wherein R¹ is phenyl or 2-pyridinyl, each optionally substituted with one or more substituents each independently selected from the group consisting of halo, C₁₋₄alkyl, monohalo-C₁₋₄alkyl, polyhalo-C₁₋₄alkyl, —CN, C₃₋₇cycloalkyl, monohalo-C₁₋₄alkyloxy, polyhalo-C₁₋₄alkyloxy, SF₅, C₁₋₄alkylthio, monohalo-C₁₋₄alkylthio and polyhalo-C₁₋₄alkylthio; R² is selected from the group consisting of hydrogen; C₁₋₄alkyl; C₃₋₇cycloalkyl; Het¹; Aryl; —C(O)R⁵; —C(O)Het²; Het²; and C₁₋₄alkyl substituted with one or more substituents each independently selected from the group consisting of halo, C3-7cycloalkyl, Aryl, Het¹ and Het²; R⁵ is selected from the group consisting of hydrogen, C₁₋₄alkyl and C₃₋₇cycloalkyl; Aryl is phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halo, C₁₋₄alkyl, monohalo-C₁₋₄alkyl, polyhalo-C₁₋₄alkyl, —CN, —OH, —C₁₋₄alkyl-O—C₁₋₄alkyl, —NR′R″, —NHC(O)C₁₋₄alkyl, —C(O)NR′R″, —C(O)NH[C(O)C₁₋₄alkyl], —S(O)₂NR′R″, —S(O)₂NH[C(O)C₁₋₄alkyl] and —S(O)₂—C₁₋₄alkyl; Het¹ is selected from the group consisting of oxetanyl, tetrahydrofuranyl and tetrahydropyranyl; Het² is (a) a 6-membered aromatic heterocyclyl substituent selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl, each of which may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, C₁₋₄alkyl, —C₁₋₄alkyl-OH, monohalo-C₁₋₄alkyl, polyhalo-C₁₋₄alkyl, —CN, —O—C₁₋₄alkyl, —OH, —C₁₋₄alkyl-O—C₁₋₄alkyl, —NR′R″, —NHC(O)C₁₋₄alkyl, —C(O)NR′R″, —C(O)NH[C(O)C₁₋₄alkyl], —S(O)₂NR′R″, —S(O)₂NH[C(O)C₁₋₄alkyl] and —S(O)₂—C₁₋₄alkyl; or (b) a 5-membered aromatic heterocyclyl selected from the group consisting of thiazolyl, oxazolyl, 1H-pyrazolyl and 1H-imidazolyl, each of which may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, C₁₋₄alkyl, —C₁₋₄alkyl-OH, monohalo-C₁₋₄alkyl, polyhalo-C₁₋₄alkyl, —CN, —O—C₁₋₄alkyl, —OH, —C₁₋₄alkyl-O—C₁₋₄alkyl, —NR′R″, —NHC(O)C₁₋₄alkyl, —C(O)NR′R″, —C(O)NH[C(O)C₁₋₄alkyl], —S(O)₂NR′R″, —S(O)₂NH[C(O)C₁₋₄alkyl] and —S(O)₂—C₁₋₄alkyl; R′ and R″ are each independently selected from the group consisting of hydrogen and C₁₋₄alkyl; R³ is selected from the group consisting of hydrogen and C₁₋₄alkyl; and R⁴ is selected from the group consisting of hydrogen, C₁₋₄alkyl, monohalo-C₁₋₄alkyl, polyhalo-C₁₋₄alkyl, —C₁₋₄alkyl-O—C₁₋₄alkyl and —C₁₋₄alkyl-OH; or a N-oxide, or a pharmaceutically acceptable salt thereof.
 2. The method of claim 1, wherein R¹ is phenyl or 2-pyridinyl, each optionally substituted with one or two substituents each independently selected from the group consisting of halo, C₁₋₄alkyl, monohalo-C₁₋₄alkyl, polyhalo-C₁₋₄alkyl, —CN, —C₁₋₄alkyl-O—C₁₋₄alkyl, —O—C₁₋₄alkyl, monohalo-C₁₋₄alkyloxy and polyhalo-C₁₋₄alkyloxy; R² is selected from the group consisting of hydrogen; C₁₋₄alkyl; C₃₋₇cycloalkyl; Het¹; Aryl; —C(O)R⁵; —C(O)Het²; Het²; and C₁₋₄alkyl substituted with one or more substituents each independently selected from the group consisting of C₃₋₇cycloalkyl, Aryl, Het¹ and Het²; Aryl is phenyl optionally substituted with a substituent selected from the group consisting of halo, C₁₋₄alkyl, —O—C₁₋₄alkyl and —S(O)₂—C₁₋₄alkyl; Het² is (a) a 6-membered aromatic heterocyclyl substituent selected from the group consisting of pyridinyl, pyrimidinyl and pyrazinyl, each of which may be optionally substituted with one or two substituents each independently selected from the group consisting of halo, C₁₋₄alkyl, —O—C₁₋₄alkyl and —NR′R″; or (b) a 5-membered aromatic heterocyclyl selected from the group consisting of thiazolyl, oxazolyl and 1H-imidazolyl, each of which may be optionally substituted with a C₁₋₄alkyl substituent; R′ and R″ are each independently selected from the group consisting of hydrogen and C₁₋₄alkyl; R³ is hydrogen; and R⁴ is selected from the group consisting of hydrogen, C₁₋₄alkyl and —C₁₋₄alkyl-O—C₁₋₄alkyl; or a N-oxide, or a pharmaceutically acceptable salt or a solvate thereof.
 3. The method of claim 1, wherein R¹ is phenyl or 2-pyridinyl, each optionally substituted with one or two substituents each independently selected from the group consisting of halo, C₁₋₄alkyl, polyhalo-C₁₋₄alkyl, —C₁₋₄alkyl-O—C₁₋₄alkyl, —O—C₁₋₄alkyl and polyhalo-C₁₋₄alkyloxy; R² is selected from the group consisting of Aryl; and Het²; Aryl is phenyl optionally substituted with a halo substituent; Het² is (a) a 6-membered aromatic heterocyclyl substituent selected from the group consisting of pyridinyl, pyrimidinyl and pyrazinyl, each of which may be optionally substituted with one or two substituents each independently selected from the group consisting of halo, C₁₋₄alkyl, —O—C₁₋₄alkyl and NR′R″; or (b) a 5-membered aromatic heterocyclyl selected from the group consisting of thiazolyl, 1,2-oxazolyl, 1,3-oxazolyl and 1H-imidazolyl, each of which may be optionally substituted with a C₁₋₄alkyl substituent; R′ and R″ are each independently hydrogen; R³ is hydrogen; and R⁴ is selected from the group consisting of hydrogen, C₁₋₄alkyl and —C₁₋₄alkyl-O—C₁₋₄alkyl; or a N-oxide, or a pharmaceutically acceptable salt thereof.
 4. The method of claim 1, wherein R¹ is phenyl or 2-pyridinyl, each optionally substituted with one or two substituents each independently selected from the group consisting of halo, C₁₋₄alkyl, polyhalo-C₁₋₄alkyl, —O—C₁₋₄alkyl and polyhalo-C₁₋₄alkyloxy; R² is selected from the group consisting of Aryl; and Het²; Aryl is phenyl optionally substituted with a halo substituent; Het² is (a) pyridinyl or pyrazinyl, each of which may be optionally substituted with one or two substituents each independently selected from the group consisting of halo, C₁₋₄alkyl, —O—C₁₋₄alkyl and NR′R″; or (b) & thiazolyl; R′ and R″ are each independently hydrogen; and R³ is hydrogen; and R⁴ is selected from the group consisting of CH₃ and CH₂OCH₃; or a N-oxide, or a pharmaceutically acceptable salt thereof.
 5. The method of claim 1, wherein the compound is of Formula (I′)

wherein R⁴ is selected from the group consisting of C₁₋₄alkyl, monohalo-C₁₋₄alkyl, polyhalo-C₁₋₄alkyl, —C₁₋₄alkyl-O—C₁₋₄alkyl and —C₁₋₄alkyl-OH or a N-oxide, or a pharmaceutically acceptable salt thereof.
 6. The method of claim 1, wherein the compound is

or a pharmaceutically acceptable salt or a solvate thereof.
 7. The method of claim 1, wherein the compound is

or a pharmaceutically acceptable salt or a solvate thereof.
 8. The method of claim 1, wherein the compound is

or a pharmaceutically acceptable salt or a solvate thereof.
 9. The method of claim 1 wherein the depressive disorder is selected from the group consisting of major depressive disorder, persistent depressive disorder (dysthymia) and substance-medication-induced depressive disorder. 